Total synthesis of taxol

ABSTRACT

The present invention provides two basic routes for the total synthesis of taxol having the structure: ##STR1## The present invention also provides the intermediates produced in the above processes, processes for synthesizing these intermediates as well as analogs to taxol. Both the intermediates and analogs to taxol may prove to be valuable anticancer agents.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced byArabic numerals within parentheses. Full citations for these referencesmay be found at the end of the specification immediately preceding theclaims. The disclosures of these publications in their entirety arehereby incorporated by reference into this application in order to morefully describe the state of the art to which this invention pertains.

The chemistry and pharmacology of the potent anticancer diterpenoidtaxol 1 (1), isolated from the yew tree, Taxus brevifolia, has beenreviewed extensively (2, 3, 4, 5). Taxol is currently undergoing phaseII trials (6) and has shown very encouraging antitumor activity,especially against ovarian and breast cancers (4, 5).

Unfortunately, the natural availability of taxol is extremely limited.The increasing demand of taxol for the treatment of patients and thedesirability of analogs to determine the real pathway of its mode ofaction has made the total synthesis or hemi-synthesis of taxol and itsanalogs a high priority over the last ten years (2, 3, 7).

Attempts at the hemi-synthesis of taxol have been based on using anextract from the leaves of the yew tree, 10-deacetylbaccatin III, as thestarting material (3). Structural modifications of taxol have also beenperformed using taxol as the starting material itself, or10-deacetylbaccatin III (3). In addition, there has been limited successin synthesizing the taxane skeleton or framework (2, 3, 7).

However, due to the complex structure of taxol, i.e. the vastfunctionalities and the buildup of the highly strained middle ringsystem, the various efforts at the total synthesis of this tetracycliccompound have not been successful (2, 3).

The inventors have overcome the difficulties faced by others and havebeen able to synthesize taxol via two routes. The present inventionprovides two basic routes for the total synthesis of taxol, importantintermediates produced therein, processes for synthesizing theseintermediates as well as analogs to taxol. Both the intermediates andanalogs to taxol may prove to be valuable anticancer agents.

SUMMARY OF THE INVENTION

The present invention provides a compound having the structure: ##STR2##wherein X is H, OH, O, or OSiR₃ ; Y is --OCH₂ CH₂ O--; R is an alkyl oraryl group.

The present invention also provides a compound having the structure:##STR3## wherein each X is independently the same or different and is H,OH, O or OSiR₃ ; Y is --OCH₂ CH₂ O--; Z is OH, O or OTMS; E is H, CN,CO₂ R, CHO or CH₂ OR'; R' is H, COR, R or SiR₃ ; and R is an alkyl oraryl group.

The present invention further provides a compound having the structure:##STR4## wherein each X is independently the same or different and is H,OH, O, or OSiR₃ ; Y is H, O, or --OCH₂ CH₂ O--; E is H, CN, CO₂ R, CHO,or CH₂ OR'; R¹ is H, OH, OCOR, OR or OSiR₃ ; and R² is H, CH₂ OSiR₃, CH₂SR, or CH₂ SOR; wherein R' is H, COR, R, or SiR₃ and R is an alkyl oraryl group.

Additionally, the present invention provides a compound having thestructure: ##STR5## wherein each X is independently the same ordifferent and is H, OH, O, OR or OSiR₃ ; Y is O or --OCH₂ CH₂ O--; E isCN, CO₂ R, CHO, or CH₂ OR'; R¹ is H, COR, or SiR₃ ; and R² is H, COR, orSiR₃ ; wherein R' is H, COR, R, or SiR₃ and R is an alkyl or aryl group.

The present invention also provides a compound having the structure:##STR6## wherein X is H, OH, O, OR, or OSiR₃ ; and R¹, R², R³, R⁴, andR⁵ are independently the same or different and are H, COR, SiR₃, or R;wherein R is an alkyl or aryl group; with the proviso that X, R¹, R²,R³, R⁴, and R⁵ are not OAc, H, Ac, COPh, H, and PhCH(BzNH)CH(OH)CO--,respectively.

The present invention also provides processes for synthesizing thecompounds above.

In addition, the present invention also provides a process forsynthesizing a compound having the structure: ##STR7## which comprises:(a) treating a compound having the structure: ##STR8## under suitableconditions to form a compound having the structure: ##STR9## (b)treating the compound formed in step (a) under suitable conditions toform a compound having the structure: ##STR10## and (c) treating thecompound formed in step (b) under suitable conditions to form thecompound having the structure: ##STR11##

The present invention also provides a compound having the structure:##STR12## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--;and R₂ and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR13## wherein X₃ and X₄ are independently the same or different andare H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS.

Moreover, the present invention provides a compound having thestructure: ##STR14## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂CH₂ CH₂ S--; R₂ and R₃ are independently the same or different and areH, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and R₄ isPhCH(BzNH)CH(OH)CO--, O, an alkyl, or aryl group; wherein R is H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR15## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--;R₂ and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; and R₄ is PhCH(BzNH)CH(OH)CO--, O,an alkyl, or aryl group; wherein R is H, acyl, alkyl, aryl, TBS, TES,TMS, or TBDPS.

The present invention further provides a compound having the structure:##STR16## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--;and R₂ and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS.

In addition, the present invention provides a compound having thestructure: ##STR17## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂CH₂ CH₂ S--; and R₁, R₂, and R₃ are independently the same or differentand are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H,acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR18## wherein X₂, X₃, and X₄ are independently the same or differentand are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₁, R₂, andR₃ are independently the same or different and are H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES,TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR19## wherein X₁, X₂, X₃, and X₄ are independently the same ordifferent and are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; andR₁, R₂, and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR20## wherein X₁ and X₅ are independently the same or different andare H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; wherein R is H,acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention further provides a compound having the structure:##STR21## wherein X₁, X₂, and X₅ are independently the same or differentand are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and M is H or ametal; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

Additionally, the present invention provides a compound having thestructure: ##STR22## wherein X₁, X₂, and X₃, are independently the sameor different and are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--;and R₂ and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS.

The present invention further provides processes for synthesizing thecompounds above.

Finally, the present invention provides a process for synthesizing acompound having the structure: ##STR23## which comprises: (a)synthesizing a compound having the structure: ##STR24## (b) treating thecompound formed in step (a) under suitable conditions to form a compoundhaving the structure: ##STR25## (c) contacting the compound formed instep (b) with lithiodithiane under suitable conditions to form acompound having the structure: ##STR26## (d) deketalizing the compoundformed in step (c) under suitable conditions to form a compound havingthe structure: ##STR27## (e) contacting the compound formed in step (d)with methoxyvinyllithium under suitable conditions to form a compoundhaving the structure: ##STR28## (f) heating the compound formed in step(e) under suitable conditions to form a compound having the structure:##STR29## (g) reducing and esterifying the compound formed in step (f)under suitable conditions to form a compound having the structure:##STR30## (h) oxidizing the compound formed in step (g) under suitableconditions to form a compound having the structure: ##STR31## (i)removing the thioketal of the compound formed in step (h) under suitableconditions to form a compound having the structure: ##STR32## (j)treating the compound formed in step (i) under suitable conditions toform a compound having the structure: ##STR33## (k) treating thecompound formed in step (j) under suitable conditions to form a compoundhaving the structure: ##STR34## and (l) treating the compound formed instep (k) under suitable conditions to form the compound having thestructure: ##STR35##

DESCRIPTION OF THE FIGURES

FIG. 1. Retrosynthetic analysis of Route 1 total synthesis of taxol. Thefunctional groups are defined as follows: R¹ =H, COR, SIR₃, or R; R²=OSiR₃, SR, or SOR; E=CN, CO₂ R, CHO, or CH₂ R'; X=H,H, H,OH, H,OSiR₃,or O; Y=O or --OCH₂ CH₂ O--; R'=H, COR, SIR₃, or R; and R=alkyl, aryl.

FIG. 2. A-ring synthesis and extension to aldehyde 5; preparation of thedienophile 7; Diels-Alder reaction with model four-carbon diene1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky's diene), andMichael addition of a cyano fragment onto the enone function of theadduct.

FIG. 3. Oxidation of dienophile 7 leading to dione 13 and Diels-Alderreaction with model four-carbon diene.

FIG. 4. Allylic oxidation of A-ring (preparation of compounds 17 and23); deketalization of A-ring (preparation of compound 19); preparationof aldehyde 21 and acetylenic compounds 22 and 24.

FIG. 5. Extension of aldehyde 5 to the trisubstituted dienophiles 28 and30.

FIG. 6. Preparation of aldehyde 5. (a) KHMDS, PhNTf₂, THF, 82%; (b) Bu₃SnCH═CH₂, cat. Pd(PPh₃)₄, THF, 91%; (c) 9-BBN, THF, 94%; (d) Swern, 94%.

FIG. 7. Preparation of compounds 7 and 10. (a) BrMgC(Me)═CH₂, THF, 89%;(b) Swern, 96%; (c) Danishefsky's diene, then H⁺, 81%; (d) p-TsOH,THF-water, 89%; (e) Et₂ AlCN, benzene, 72%.

FIG. 8. Preparation of compounds 12 and 15. (a) KHMDS, F. Davisoxaziridine, 87%; (b) Danishefsky's diene, then H⁺, 95%; (c) Swern, 69%;(d) H⁺, p-TsOH, THF-water, 79%.

FIG. 9. Preparation of compounds 25, 26, 28, and 30. (a) CrCl₂, cat.NiCl₂, DMF, 60-70%; (b) Swern, 82-88%.

FIG. 10. Preparation of compounds 18 and 23. (a) TBDMSCl, NEt₃, CH₂ Cl₂,76%; (b) CrO₃ -3,5-DMP, CH₂ Cl₂, 37-48%; (c) p-TsOH, Me₂ CO, water, 82%.

FIG. 11. Preparation of compounds 19, 21, 22, and 24.

FIG. 12A-12D. Total synthesis of Taxol.

FIG. 13. Retrosynthetic analysis of Route 2(a) total synthesis of taxol.

FIG. 14. Retrosynthetic analysis of Route 2(b) total synthesis of taxol.

FIG. 15. Preparation of compounds 68 and 69. (a) TBSOTf/2,6-lutidine/CH₂Cl₂ /0° C.;97%; (b) i) BH₃ -THF ii) H₂ O₂ /NaOH; (c) 10 mol %TPAP/NMO/powdered 4 Å molecular sieves/CH₂ Cl₂ ; (d) 3% NaOMe in MeOH;76% overall for steps b-d; (e) i) KHMDS/THF/-78° C./30 min ii) PhNTf₂/-78° C./1 h; 81%; (f) DMF/3 eq. Hunig's base/40 eq. anh. MeOH/8 mol %Pd(OAc)₂ /16 mol % Ph₃ P/2 psi CO/4 h; 73%; (g) DIBAH/hexanes/-78% °C.;99%; (h) 5 mol % OsO₄ /NMO/acetone/H₂ O; 66%; (i) i) TMSCl/pyr/CH₂ Cl₂/-78° C. to rt ii) Tf₂ O/-78° C. to rt iii) ethylene glycol/40° C./12 h;69% overall; (j) TBAF/THF/reflux/10 h; 93%; (k) 1 eq. collidiumtosylate/acetone:H₂ O (12:1)/reflux/120 h; 84%; (1) i) 2 eq.LDA/THF/-78° C./1.5 h ii) 2.3 eq. TMSCl/-78° to rt; (m) i) 1.1 eq.Pd(OAc)₂ /MeCN/reflux ii) MeOH/K₂ CO₃ ; 77% overall; (n)TBSCl/imidazole/DMF/80° C.; 57%; (o) TMSCl/pyr/CH₂ Cl₂ ; 88%; (p) i)KHMDS/THF/-78° C. ii) N-phenylsulfonyl phenyloxaziridine iii) H₂ O/-78°C. to rt; 77%; (q) i) LDA/THF/-78° C. ii) TMSCl/-78° C. to rt (r) i) O₃/CH₂ Cl₂ /-78° C. ii) Ph₃ P/-78° C. to rt; 36%.

FIG. 16. Total synthesis of taxol from dialdehyde 69. (a) ethyleneglycol, PPTS; (b) i) XVII (X₂ =SCH₂ CH₂ CH₂ S; M=Li); ii) Swern; (c)acetone, PPTS; (d) i) X (R₁ =MOM; M=Li); ii) Swern; (e) xylene, reflux;(f) i) NaBH₄ ; ii) BzCl/pyr; (g) i) SeO₂ /dioxane; ii) Swern; (h) i)L-selectride; ii) BnBr/NaH; iii) Raney Ni; (i) i) KHMDS; then N-phenylphenylsulfonyloxaziridine; ii) TBAF; iii) Ac₂ O/pyr/DMAP; (j) i) H₂/Pd-C; ii) See (49); (k) LiOH/H₂ O/THF; (1) dilute acid/H₂ O.

FIG. 17. Mimics of taxol. (a) Ac₂ O/Pyr; (b) L-selectride/THF/78° C.;(c) See (49); (d) TBAF/THF; (e) dilute acid/H₂ O; (f) BzCl/pyr.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound having the structure:##STR36## wherein X is H, OH, O, or OSiR₃ ; Y is --OCH₂ CH₂ O--; R is analkyl or aryl group.

The present invention also provides a compound having the structure:##STR37## wherein each x is independently the same or different and isH, OH, O or OSiR₃ ; Y is --OCH₂ CH₂ O--; Z is OH, O or OTMS; E is H, CN,CO₂ R, CHO or CH₂ OR'; R' is H, COR, R or SiR₃ ; R is an alkyl or arylgroup.

The present invention further provides a compound having the structure:##STR38## wherein each X is independently the same or different and isH, OH, O, or OSiR₃ ; Y is H, O, or --OCH₂ CH₂ O--; E is H, CN, CO₂ R,CHO, or CH₂ OR'; R¹ is H, OH, OCOR, OR or OSiR₃ ; and R² is H, CH₂OSiR₃, CH₂ SR, or CH₂ SOR; wherein R' is H, COR, R, or SiR₃ and R is analkyl or aryl group.

As used herein, a bond denoted by a solid line juxtaposed to a dashedline represents (a) a double bond if terminated only by O; (b) a singlebond if terminated by H, OH or OSiR₃ ; and (c) two single bonds ifterminated by --OH₂ CH₂ O--.

Additionally, the present invention provides a compound having thestructure: ##STR39## wherein each X is independently the same ordifferent and is H, OH, O, OR or OSiR₃ ; Y is O or --OCH₂ CH₂ O--; E isCN, CO₂ R, CHO, or CH₂ OR'; R¹ is H, COR, or SiR₃ ; and R₂ is H, COR, orSiR₃ ; wherein R' is H, COR, R, or SiR₃ and R is an alkyl or aryl group.

The present invention also provides a compound having the structure:##STR40## wherein X is H, OH, O, OR, or OSiR₃ ; and R¹, R², R³, R⁴, andR⁵ are independently the same or different and are H, COR, SiR₃, or R;wherein R is an alkyl or aryl group; with the proviso that X, R¹, R²,R³, R⁴, and R⁵ are not OAc, H, Ac, COPh, H, and PhCH(BzNH)CH(OH)CO--,respectively.

The present invention also provides a process for synthesizing analdehyde having the structure: ##STR41## wherein Y is O or --OCH₂ CH₂O--; which comprises: (a) triflating a ketoketal having the structure:##STR42## wherein Y is O or --OCH₂ CH₂ O--; under suitable conditions toform an enol triflate having the structure: ##STR43## (b) reacting theenol triflate formed in step (a) with vinyltributylstannane underpalladium (O) catalysis, under suitable conditions to form a dienehaving the structure: ##STR44## (c) reacting the diene formed in step(b) by hydroboration/oxidation under suitable conditions to form analcohol having the structure: ##STR45## (d) contacting the alcoholformed in step (c) with a first protecting group under suitableconditions to form a protected alcohol having the structure: ##STR46##(e) oxidizing the protected alcohol formed in step (d) under suitableconditions to form an enone having the structure: ##STR47## (f) reducingthe enone formed in step (e) under suitable conditions to form anallylic alcohol having the structure: ##STR48## (g) contacting theallylic alcohol formed in step (f) with a second protecting group undersuitable conditions to form a protected alcohol having the structure:##STR49## (h) treating the protected alcohol formed in step (g) undersuitable conditions to selectively remove the first protecting group toform an alcohol having the structure: ##STR50## and (i) oxidizing thealcohol formed in step (h) to form the aldehyde having the structure:##STR51##

In the above process and the various processes which follow, thesuitable conditions necessary for the various reactions and treatmentsmay be found in the Experimental Details Section which follows. However,it is within the confines of the present invention that the specificreactants and solvents provided as well as the specific conditionsnecessary for reaction or treatment may be substituted with othersuitable reactants, solvents and conditions well known to those skilledin the art.

In step (a) above, the "triflating" of the ketoketal is performed byreacting the ketoketal with a suitable triflating agent, preferably,N-phenyl-trifluoromethane sulfonimide. In step (b) above, the enoltriflate formed in step (a) is coupled under palladium (O) catalysiswith vinyl-tri-n-butylstannane leading to the diene. In step (c), thediene is preferably hydroborated with 9-BBN, to give, after basichydroperoxide work-up, the alcohol. In step (d), the alcohol is treatedwith a protecting group, preferably TBDMSCl, or another suitableprotecting group to form the protected alcohol. In step (e), theoxidizing of the protected alcohol is preferably performed via3,5-dimethylpyrazole mediated allylic oxidation in the presence of achromium trioxide complex. In step (f), the enone is preferably reducedwith borane in the presence of a catalytic amount of chiraloxazoborolidine to give the allylic alcohol. In step (g), the alcoholfunction of the allylic alcohol is preferably protected with a TBDMSgroup. In step (h), the first protecting group is preferably removed byselective desilylation of the primary hydroxyl. In step (i), the alcoholis preferably oxidized by the method of Swern to form the aldehyde.

The present invention also provides a process for synthesizing a diketodienophile having the structure: ##STR52## wherein Y is O or --OCH₂ CH₂O--; and E is --CH₂₀ R', CN, CO₂ R, or CHO; wherein R' is H, COR, R, orSiR₃ and R is an alkyl or aryl group; which comprises:

(a) synthesizing an aldehyde having the structure: ##STR53## accordingto the process above; (b) coupling the aldehyde formed in step (a) witha compound having the structure: ##STR54## wherein E is --CH₂ OR', CN,CO₂ R, or CHO; wherein R' is H, COR, R, or SiR₃ and R is an alkyl oraryl group; under suitable conditions to form an allylic alcohol havingthe structure: ##STR55## (c) oxidizing the allylic alcohol formed instep (b) under suitable conditions to form an enone having thestructure: ##STR56## (d) treating the enone formed in step (c) undersuitable conditions to form a hydroxyketone having the structure:##STR57## and (e) oxidizing the hydroxyketone formed in step (d) undersuitable conditions to form the diketo dienophile having the structure:##STR58##

In step (a) above, the aldehyde may be synthesized by the previousprocess or other processes determinable by those skilled in the art. Instep (b), the coupling is preferably performed by a nickel chloridecatalyzed chromium (II) chloride promoted coupling of the iodidecompound, preferably vinyl iodide, with the aldehyde to afford theallylic alcohol. In step (c), the alcohol is preferably oxidized bySwern oxidation (oxalyl chloride, dimethylsulfoxide, triethylamine,dichloromethane) to form the enone, which is converted in step (d) intothe hydroxyketone by preferably adding KHMDS followed byN-phenylsulfonyl-phenyloxaziridine. In step (e), the hydroxyketone ispreferably oxidized using oxalyl chloride and DMSO followed bytriethylamine to form the diketo dienophile.

The present invention also provides a process for synthesizing acompound having the structure: ##STR59## wherein Y is O or --OCH₂ CH₂O--; E is --CH₂ OR', CN, CO₂ R, or CHO; R¹ is H, COR, R, or SiR₃ ; andR² is OSiR₃, SR, or SOR; wherein R' is H, COR, R, or SiR₃ and R is analkyl or aryl group; which comprises:

(a) synthesizing a diketo dienophile having the structure: ##STR60##according to the process above; and (b) coupling the diketo dienophileformed in step (a) with a diene having the structure: ##STR61## whereinR¹ is H, COR, R, or SiR₃ ; and R² is OSiR₃, SR, or SOR; wherein R is analkyl or aryl group; to form the compound having the structure:##STR62##

In step (a) above, the diketo dienophile may be synthesized by theprevious process or other processes determinable by those skilled in theart. In step (b), Diels-Alder cycloaddition of the diketo dienophilewith the diene followed by acidic work-up yields an adduct in which theprimary silyl ether is selectively cleaved affording the alcohol.Alternatively, fluoride mediated work-up of the Diels-Alder reactionbetween the diketo dienophile and the diene produces the compounddirectly.

The present invention also provides a process for synthesizing acompound having the structure: ##STR63## wherein R¹ is H, COR, R, orSiR₃ ; and R² is OSiR₃, SR, or SOR; wherein R is an alkyl or aryl group;which comprises:

(a) synthesizing a compound having the structure: ##STR64## according tothe process above; (b) oxidizing the compound formed in step (a) undersuitable conditions to form an aldehyde having the structure: ##STR65##and (c) deketalizing the aldehyde formed in step (b) under suitableconditions to form the compound having the structure: ##STR66##

In step (a) above, the compound may be synthesized by the previousprocess or other processes determinable by those skilled in the art. Instep (b), the compound of step (a) is preferably oxidized using oxalylchloride and DMSO followed by triethylamine to form the aldehyde. Instep (c), the deketalizaton preferably involves treating the ketal withp-toluenesulfonic acid in aqueous tetrahydrofuran to form the compoundin which the protecting group, preferably the TBDMS ether, isconcomitantly removed.

The present invention also provides a process for synthesizing acompound having the structure: ##STR67## wherein X is OH or O; R¹ is H,COR, R, or SiR₃ ; and R² is OSiR₃, SR, or SOR; wherein R is an alkyl oraryl group; which comprises:

(a) synthesizing a compound having the structure: ##STR68## according tothe process above; and (b) coupling the compound formed in step (a) byintramolecular pinacolic coupling under suitable conditions to form acompound having the structure: ##STR69##

In step (a) above, the compound may be synthesized by the previousprocess or other processes determinable by those skilled in the art. Instep (b), the pinacolic coupling preferably involves the samariumdiiodide promoted intramolecular coupling which is assisted by both thepresence of the free hydroxyl group at C-13 (numbering refers to thetaxol skeleton), and the cyclic enediolate samarium species, formed bythe complexation of the diketo system at C-9,10 with excess reagent.Concomitantly, the ketone at C-5 might be reduced.

The present invention also provides a process for synthesizing acompound having the structure: ##STR70## wherein R¹ is H, COR, R, orSiR₃ ; wherein R is an alkyl or aryl group; which comprises:

(a) synthesizing a compound having the structure: ##STR71## according tothe process above; (b) treating the compound formed in step (a) undersuitable conditions to form a compound having the structure: ##STR72##(c) oxidizing the compound formed instep (b) under suitable conditionsto form a compound having the structure: ##STR73## (d) reducing thecompound formed in step (c) under suitable conditions to form a compoundhaving the structure: ##STR74## (e) treating the compound formed in step(d) under suitable conditions to form a compound having the structure:##STR75## and (f) treating the compound formed in step (e) undersuitable conditions to form the compound having the structure: ##STR76##

In step (a) above, the compound may be synthesized by the previousprocess or other processes determinable by those skilled in the art. Instep (b), sequential selective protection of the hydroxyl groups,preferably by the addition of Ac₂ O/Py, TMSCl/NEt₃, TBDMSCl/NEt₃, andH⁺, of the compound synthesized in step (a) at C-10, C-1 (temporary) andC-13, leads to the formed compound. In step (c), the compound ispreferably oxidized using oxalyl chloride and DMSO followed bytriethylamine. In step (d), α-hydroxy at C-2 is preferablystereoselectively reduced using Zn(BH₄)₂. In step (e), the compound issequentially protected, preferably by the addition of TMSCl/NEt₃,BzCl/Py, H⁺, and NaH/BnBr. In step (f), the treating preferablycomprises the reduction at C-5, the oxidation of the sulfide at C-20 tothe sulfoxide and its elimination upon heating, followed by the osmiumtetroxide catalyzed bis-hydroxylation of the allylic alcohol.

The present invention also provides a process for synthesizing acompound having the structure: ##STR77## which comprises: (a)synthesizing a compound having the structure: ##STR78## according to theprocess above; and (b) treating the compound formed in step (a) undersuitable conditions to form the compound having the structure: ##STR79##

In step (a) above, the compound may be synthesized by the previousprocess or other processes determinable by those skilled in the art. Instep (b), the compound of step (a) is converted to the hydroxy oxetaneby known procedures (11,12).

The present invention also provides a process for synthesizing acompound having the structure: ##STR80## which comprises: (a)synthesizing a compound having the structure: ##STR81## according to theprocess of above; (b) treating the compound formed in step (a) undersuitable conditions to form a compound having the structure: ##STR82##(c) treating the compound formed in step (a) under suitable conditionsto form a compound having the structure: ##STR83## and (d) treating thecompound formed in step (c) under suitable conditions to form a compoundhaving the structure: ##STR84##

In step (a) above, the compound may be synthesized by the previousprocess or other processes known to those skilled in the art. In step(b), the hydroxy group at C-4 and the protecting group, TBDMSO, at C-13are readily converted into corresponding acetoxy and hydroxy groups bythe addition of Ac₂ O/Py. and TBAF. In step (c), the side chainattachment at C-13 is accomplished by known protocols (49). In step (d),the sequential selective deprotection of hydroxyl groups at C-1 and C-7by adding H₂ /Pd/C produces taxol.

In addition, the present invention also provides a process forsynthesizing a compound having the structure: ##STR85## which comprises:(a) treating a compound having the structure: ##STR86## under suitableconditions to form a compound having the structure: ##STR87## (b)treating the compound formed in step (a) under suitable conditions toform a compound having the structure: ##STR88## and (c) treating thecompound formed in step (b) under suitable conditions to form thecompound having the structure: ##STR89##

In step (a), the hydroxy group at C-4 and the protecting group, TBDMSO,at C-13 are readily converted into corresponding acetoxy and hydroxygroups by the addition of Ac₂ O/Py. and TBAF. In step (b), the sidechain attachment at C-13 is accomplished by known protocols (49). Instep (c), the sequential selective deprotection of hydroxyl groups atC-1 and C-7 by adding H₂ /Pd/C produces taxol.

The present invention also provides a process for synthesizing acompound having the structure: ##STR90## which comprises treating acompound having the structure: ##STR91## under suitable conditions toform the compound having the structure: ##STR92##

In process above, the starting compound is converted to the hydroxyoxetane by known procedures (11,12).

The present invention also provides a process for synthesizing acompound having the structure: ##STR93## wherein R¹ is H, COR, R, orSiR₃ ; wherein R is an alkyl or aryl group; which comprises:

(a) treating a compound having the structure: ##STR94## wherein X is Oor OH; and R¹ is H, COR, R, or SiR₃ ; wherein R is an alkyl or arylgroup; under suitable conditions to form a compound having thestructure: ##STR95## (b) oxidizing the compound formed in step (a) undersuitable conditions to form a compound having the structure: ##STR96##(c) reducing the compound formed in step (b) under suitable conditionsto form a compound having the structure: ##STR97## (d) treating thecompound formed in step (c) under suitable conditions to form a compoundhaving the structure: ##STR98## and (e) treating the compound formed instep (d) under suitable conditions to form the compound having thestructure: ##STR99##

In step (a), sequential selective protection of the hydroxyl groups,preferably by the addition of Ac₂ O/Py, TMSCl/NEt₃, TBDMSCl/NEt₃, andH⁺, of the starting compound at C-10, C-1 (temporary) and C-13, leads tothe formed compound. In step (b), the compound is preferably oxidizedusing oxalyl chloride and DMSO followed by triethylamine. In step (c),α-hydroxy at C-2 is preferably stereoselectively reduced using Zn(BH₄)₂.In step (d), the compound is sequentially protected, preferably by theaddition of TMSCl/NEt₃, BzCl/Py, H⁺, and NaH/BnBr. In step (e), thetreating preferably comprises the reduction at C-5, the oxidation of thesulfide at C-20 to the sulfoxide, and its elimination upon heating,followed by the osmium tetroxide catalyzed bis-hydroxylation of theallylic alcohol.

The present invention also provides a process for synthesizing acompound having the structure: ##STR100## wherein R¹ is H, COR, R, orSiR₃ ; R² is OSiR₃, SR, or SOR; and X is OH or O; wherein R is an alkylor aryl group; which comprises coupling a compound having the structure:##STR101## wherein R¹ is H, COR, R, or SiR₃ ; and R² is OSiR₃, SR, orSOR; wherein R is an alkyl or aryl group; by intramolecular pinacoliccoupling under suitable conditions to form a compound having thestructure: ##STR102##

In process above, the pinacolic coupling preferably involves thesamarium diiodide promoted intramolecular coupling which is assisted byboth the presence of the free hydroxyl group at C-13 (numbering refersto the taxol skeleton), and the cyclic enediolate samarium species,formed by the complexation of the diketo system at C-9,10 with excessreagent. Concomitantly, the ketone at C-5 might be reduced.

The present invention also provides a process for synthesizing acompound having the structure: ##STR103## wherein R¹ is H, COR, R, orSiR₃ ; and R² is OSiR₃, SR, or SOR; wherein R is an alkyl or aryl group;which comprises:

(a) oxidizing a compound having the structure: ##STR104## wherein R¹ isH, COR, R, or SiR₃ ; and R² is OSiR₃, SR, or SOR; wherein R is an alkylor aryl group; under suitable conditions to form an aldehyde having thestructure: ##STR105## and (b) deketalizing the aldehyde formed in step(a) under suitable conditions to form the compound having the structure:##STR106##

In step (a), the starting compound is preferably oxidized using oxalylchloride and DMSO followed by triethylamine to form the aldehyde. Instep (b), the deketalizaton preferably involves treating the ketal withp-toluenesulfonic acid in aqueous tetrahydrofuran to form the compoundin which the protecting group, preferably the TBDMS ether, isconcomitantly removed.

The present invention further provides a process for synthesizing acompound having the structure: ##STR107## wherein Y is O or --OCH₂ CH₂O--; E is --CH₂ OR', CN, CO₂ R or CHO; R¹ is H, COR, R, or SiR₃ ; and R²is OSiR₃, SR, or SOR; wherein R' is H, COR, R, or SiR₃ and R is an alkylor aryl group; which comprises coupling a diketo dienophile having thestructure: ##STR108## wherein Y is O or --OCH₂ CH₂ O--; and E is --CH₂OR', CN, CO₂ R or CHO; wherein R' is H, COR, R, or SiR₃ and R is analkyl or aryl group; with a diene having the structure: ##STR109##wherein R¹ is H, COR, R, or SiR₃ ; and R² is OSiR₃, SR, or SOR; whereinR is an alkyl or aryl group; to form the compound having the structure:##STR110##

In process above, Diels-Alder cycloaddition of the diketo dienophilewith the diene followed by acidic work-up yields an adduct in which theprimary silyl ether is selectively cleaved affording the alcohol.Alternatively, fluoride mediated work-up of the Diels-Alder reactionbetween the diketo dienophile and the diene produces the compounddirectly.

The present invention also provides a process for synthesizing a diketodienophile having the structure: ##STR111## wherein Y is O or --OCH₂ CH₂O--; and E is --CH₂ OR', CN, CO₂ R, or CHO; wherein R' is H, COR, R, orSiR₃ and R is an alkyl or aryl group; which comprises:

(a) coupling an aldehyde having the structure: ##STR112## wherein Y is Oor --OCH₂ CH₂ O--; with a compound having the structure: ##STR113##wherein E is --CH₂ OR', CN, CO₂ R or CHO; wherein R' is H, COR, R, orSiR₃ and R is an alkyl or aryl group; under suitable conditions to forman allylic alcohol having the structure: ##STR114## (b) oxidizing theallylic alcohol formed in step (a) under suitable conditions to form anenone having the structure: ##STR115## (c) treating the enone formed instep (b) under suitable conditions to form a hydroxyketone having thestructure: ##STR116## and (d) oxidizing the hydroxyketone formed in step(c) under suitable conditions to form the diketo dienophile having thestructure: ##STR117##

In step (a), the coupling is preferably performed by a nickel chloridecatalyzed chromium (II) chloride promoted coupling of the iodidecompound, preferably vinyl iodide, with the aldehyde to afford theallylic alcohol. In step (b), the alcohol is preferably oxidized bySwern oxidation (oxalyl chloride, dimethylsulfoxide, triethylamine,dichloromethane) to form the enone, which is converted in step (c) intothe hydroxyketone by preferably adding KHMDS followed byN-phenylsulfonyl-phenyloxaziridine. In step (d), the hydroxyketone ispreferably oxidized using oxalyl chloride and DMSO followed bytriethylamine to form the diketo dienophile.

The present invention also provides a process for synthesizing acompound having the structure: ##STR118## wherein each X isindependently the same or different and is H, OH, O, OR, or OSiR₃ ; Y isO or --OCH₂ CH₂ O--; and E is H, --CH₂ OR', CN, CO₂ R, or CHO; whereinR' is H, COR, R, or SiR₃ and R is an alkyl or aryl group; whichcomprises coupling an aldehyde having the structure: ##STR119## whereinX is H, OH, O, OR, or OSiR₃ ; and Y is O or --OCH₂ CH₂ O--; wherein R isan alkyl or aryl group; with a compound having the structure: ##STR120##wherein E is --CH₂ OR', CN, CO₂ R, or CHO; wherein R' is H, COR, R, orSiR₃ and R is an alkyl or aryl group; under suitable conditions to formthe compound having the structure: ##STR121##

The present invention also provides a process for synthesizing acompound having the structure: ##STR122## wherein each X isindependently the same or different and is H, OH, O, OR, or OSiR₃ ; Y isO or --OCH₂ CH₂ O--; E is H, --CH₂ OR', CN, CO₂ R, or CHO; R¹ is H, COR,R, or SiR₃ ; and R² is OSiR₃, SR, or SOR; wherein R' is H, COR, R, orSiR₃ and R is an alkyl or aryl group; which comprises contacting acompound having the structure: ##STR123## wherein each X isindependently the same or different and is H, OH, O, OR, or OSiR₃ ; Y isO or --OCH₂ CH₂ O--; and E is H, --CH₂ OR', CN, CO₂ R, or CHO; whereinR' is H, COR, R, or SiR₃ and R is an alkyl or aryl group; with acompound having the structure: ##STR124## wherein R¹ is H, COR, R, orSiR₃ ; and R² is OSiR₃, SR, or SOR; wherein R is an alkyl or aryl group;under suitable conditions to form the compound having the structure:##STR125##

The present invention also provides a process for synthesizing acompound having the structure: ##STR126## wherein each X isindependently the same or different and is H, OH, O, OR, or OSiR₃ ; Y isO or --OCH₂ CH₂ O--; E is H, --CH₂ OR', CN, CO₂ R, or CHO; R¹ is H, COR,or SiR₃ ; and R² is H, COR, or SiR₃ ; wherein R' is H, COR, R, or SiR₃and R is an alkyl or aryl group; which comprises treating a compoundhaving the structure: ##STR127## wherein each X is independently thesame or different and is H, OH, O, OR, or OSiR₃ ; Y is O or --OCH₂ CH₂O--; E is H, --CH₂ OR', CN, CO₂ R, or CHO; R¹ is H, COR, R, or SiR₃ ;and R² is OSiR₃, SR, or SOR; wherein R' is H, COR, R, or SiR₃ and R isan alkyl or aryl group; under suitable conditions to form the compoundhaving the structure: ##STR128##

The present invention also provides a process for synthesizing acompound having the structure: ##STR129## wherein X is H, OH, O, OR, orOSiR₃ ; and R¹, R², R³, R⁴, and R⁵ are independently the same ordifferent and are H, COR, SiR₃, or R; wherein R is an alkyl or arylgroup; which comprises treating a compound having the structure:##STR130## wherein each X is independently the same or different and isH, OH, O, OR, or OSiR₃ ; Y is O or --OCH₂ CH₂ O--; E is H, --CH₂ OR',CN, CO₂ R, or CHO; R¹ is H, COR, or SiR₃ ; and R² is H, COR, or SiR₃ ;wherein R' is H, COR, R, or SiR₃ and R is an alkyl or aryl group; undersuitable conditions to form the compound having the structure:##STR131##

The present invention also provides a compound having the structure:##STR132## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂S--; and R₂ and R₃ are independently the same or different and are H,acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl,aryl, TBS, TES, TMS, or TBDPS.

The present invention further provides a compound having the structure:##STR133## wherein X₃ and X₄ are independently the same or different andare H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS.

In addition, the present invention provides a compound having thestructure: ##STR134## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂CH₂ CH₂ S--; R₂ and R₃ are independently the same or different and areH, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and R₄ isPhCH(BzNH)CH(OH)CO--, O, an alkyl, or aryl group; wherein R is H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR135## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂S--; R₂ and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; and R₄ is PhCH(BzNH)CH(OH)CO--, O,an alkyl, or aryl group; wherein R is H, acyl, alkyl, aryl, TBS, TES,TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR136## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂S--; and R₂ and R₃ are independently the same or different and are H,acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl,aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR137## wherein X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂S--; and R₁, R₂, and R₃ are independently the same or different and areH, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention further provides a compound having the structure:##STR138## wherein X₂, X₃, and X₄ are independently the same ordifferent and are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; andR₁, R₂, and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS.

Moreover, the present invention provides a compound having thestructure: ##STR139## wherein X₁, X₂, X₃, and X₄ are independently thesame or different and are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂S--; and R₁, R₂, and R₃ are independently the same or different and areH, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR140## wherein X₁ and X₅ are independently the same or different andare H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; wherein R is H,acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:##STR141## wherein X₁, X₂, and X₅ are independently the same ordifferent and are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and Mis H or a metal; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS.

The present invention further provides a compound having the structure:##STR142## wherein X₁, X₂, and X₃ are independently the same ordifferent and are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; andR₂ and R₃ are independently the same or different and are H, acyl,alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS.

The present invention also provides a process for synthesizing acompound having the structure: ##STR143## wherein R is H or TBS; whichcomprises: (a) treating a compound having the structure: ##STR144##under suitable conditions to form a compound having the structure:##STR145## (b) contacting the compound formed in step (a) with TBS undersuitable conditions to form a compound having the structure: ##STR146##(c) contacting the compound formed in step (b) under suitable conditionsto form a compound having the structure: ##STR147## (d) triflating thecompound formed in step (c) under suitable conditions to form a compoundhaving the structure: ##STR148## (e) treating the compound, formed instep (d) by carbomethoxylation under suitable conditions to form acompound having the structure: ##STR149## (f) reducing the compoundformed in step (e) under suitable conditions to form a compound havingthe structure: ##STR150## (g) treating the compound formed in step (f)by oxmylation under suitable conditions to form a compound having thestructure: ##STR151## and (h) contacting the compound formed in step (g)under suitable conditions to form the compound having the structure:##STR152##

In step (a), the starting compound is treated by deconjugativeketalization and hydroboration/oxidation. In step (b), the equatorialsecondary alcohol of the compound formed in step (a) (a pro C-7 hydroxylin the C-ring of taxol) is protected by treating witht-butyldimethylsilyl (TBS) ether. In step (c), the treating comprisesthe hydroboration/oxidization of the compound formed in step (b)according to the reported protocol (33), followed by tetrapropylammoniumperruthenate catalyzed oxidation (39, 40) to give the cis andtrans-fused ketones which converge to the trans compound after basecatalyzed equilibration. In step (d), for the purpose of one carbonhomologation, the compound formed in step (c) is converted to the enoltriflate, preferably by O-sulfonylation of its potassium enolate withN-phenyltrifluoromethane sulfonimide (41, 42, 43). In step (e), thetreating comprises palladium catalyzed carbomethoxylation (44) to yieldthe unsaturated ester. In step (f), this ester is readily reduced with areducing agent, preferably, DIBAH, to the corresponding allylic alcohol.In step (g), the treating comprises the osmylation of the alcohol undercatalytic conditions to yield the triol. In step (h), the triol isconverted to the oxetane by preferably treating with TMSCl/pyridine inCH₂ Cl₂, Tf₂ O, and ethylene glycol (45). The TBS ether is removed withtetrabutylammonium fluoride.

The present invention also provides a process for synthesizing acompound having the structure: ##STR153## which comprises: (a)synthesizing a compound having the structure ##STR154## according to theprocess above; (b) removing the ketal of the compound formed in step (a)under suitable conditions to form a compound having the structure:##STR155## (c) treating the compound formed in step (b) under suitableconditions to form a compound having the structure: ##STR156## (d)treating the compound formed in step (c) under suitable conditions toform a compound having the structure: ##STR157## and (e) treating thecompound formed in step (d) under suitable conditions to form thecompound having the structure: ##STR158##

In step (a), the compound is synthesized by the process above or otherprocesses determinable by those skilled in the art. In step (b), theketal is removed under mildly acidic conditions (collidinium tosylate)to maintain the integrity of both the TBS ether and the oxetane ring. Instep (c), the ketone is subsequently converted to the correspondingenone by treating its silyl enol ether (46) with Pd(OAc)₂ (47, 48). Instep (d), the tertiary alcohol of the compound is protected with TBS bytreating with an excess of TBSCl, followed by the treatment of potassiumbis(trimethylsilyl) amide in step (e).

The present invention also provides a process for synthesizing acompound having the structure: ##STR159## which comprises: (a)synthesizing a compound having the structure ##STR160## according to thesuitable process above; (b) treating the compound formed in step (a)under suitable conditions to form a compound having the structure:##STR161## (c) treating the compound formed in step (b) under suitableconditions to form a compound having the structure: ##STR162##

In step (a), the compound is synthesized by the relevant process aboveor other processes determinable by those skilled in the art. In step(b), the treating is effected by treatment with TBSCl/imidazole/DMF. Instep (c), the treating is effected by degradation of the compound formedin step (b) to the dialdehyde by ozonolysis of the trimethylsilyl dienolether.

The present invention also provides a process for synthesizing acompound having the structure: ##STR163## wherein X₄ is H, OR, O, --OCH₂CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independently the sameor different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whichcomprises treating a compound having the structure: ##STR164## whereinX₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; under suitable conditions to form the compound having thestructure: ##STR165##

In the process above, the treating comprises methyllithium (Et₂ O/-78°C.) addition.

The present invention also provides a process for synthesizing acompound having the structure: ##STR166## wherein X₄ is H, OR, O, --OCH₂CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independently the sameor different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whichcomprises treating a compound having the structure: ##STR167## whereinX₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; under suitable conditions to form the compound having thestructure: ##STR168##

The present invention also provides a process for synthesizing acompound having the structure: ##STR169## wherein X₄ is H, OR, O, --OCH₂CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃ are independently thesame or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR170## wherein X₄is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; according to the suitable process above;

and (b) treating the compound formed in step (a) under suitableconditions to form the compound having the structure: ##STR171##

In step (a), the compound may be synthesized by the relevant processabove or other processes determinable by those skilled in the art. Thetreating in step (b) involves degradation by ozonolysis followed by leadtetraacetate.

The present invention also provides a process for synthesizing acompound having the structure: ##STR172## wherein X₃ and X₄ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR173## wherein X₄is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; according to the suitable process above;

and (b) treating the compound formed in step (a) under suitableconditions to form the compound having the structure: ##STR174##

In step (a), the compound may be synthesized by the relevant processabove or other processes determinable by those skilled in the art. Thetreating in step (b) involves homologation by methoxymethylene Wittigfollowed by oxidation.

The present invention also provides a process for synthesizing acompound having the structure: ##STR175## wherein X₂, X₃, and X₄ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR176## wherein X₄is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃are independently the same or different and are H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES,TMS, or TBDPS; according to the suitable process above;

and (b) contacting the compound formed in step (a) with a compoundhaving the structure: ##STR177## wherein X₂ is H, OR, O, --OCH₂ CH₂ O--,or --SCH₂ CH₂ CH₂ S--; and M is a metal; wherein R is H, acyl, alkyl,aryl, TBS, TES, TMS, or TBDPS; under suitable conditions to form thecompound having the structure: ##STR178##

In step (a), the compound may be synthesized by the suitable processabove or other processes determinable by those skilled in the art. Thecontacting in step (b) comprises the nucleophilic attack of the compoundsynthesized in step (a) with the compound in step (b).

The present invention also provides a process for synthesizing acompound having the structure: ##STR179## wherein X₂, X₃, and X₄ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR180## wherein X₃and X₄ are independently the same or different and are H, OR, O, --OCH₂CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independently the sameor different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according tothe suitable process above;

(b) contacting the compound formed in step (a) with a compound havingthe structure: ##STR181## wherein M is a metal; under suitableconditions to form the compound having the structure: ##STR182## whereinX₂, X₃, and X₄ are independently the same or different and are H, OR, O,--OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independentlythe same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

and (c) contacting the compound formed in step (b) with a compoundhaving the structure: ##STR183## wherein R₁ is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS; and M is a metal; under suitable conditions toform the compound having the structure: ##STR184##

In step (a), the compound may be synthesized by the suitable processabove or other processes determinable by those skilled in the art. Thecontacting in step (b) involves the addition of the metallated diene tothe aldehyde function of the compound formed in step (a). The contactingin step (c) involves the addition of the two carbon acyl-anion to thecompound formed in step (b).

The present invention also provides a process for synthesizing acompound having the structure: ##STR185## wherein X₂, X₃, and X₄ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR186## wherein X₄is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; according to the suitable process above;

(b) contacting the compound formed in step (a) with a compound havingthe structure: ##STR187## wherein X₂ is H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and M is a metal; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS; under suitable conditions to form the compoundhaving the structure: ##STR188## wherein X₂, X₃, and X₄ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

and (c) contacting the compound formed in step (b) with a compoundhaving the structure: ##STR189## wherein R₁ is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS; and M is a metal; under suitable conditions toform the compound having the structure: ##STR190##

In step (a), the compound may be synthesized by the suitable processabove or other processes determinable by those skilled in the art. Thecontacting in step (b) involves the addition of the metallated diene tothe aldehyde function of the compound formed in step (a). The contactingin step (c) involves the addition of the two carbon acyl-anion,preferably, methoxyvinyllithium, to the compound formed in step (b).

The present invention also provides a process for synthesizing acompound having the structure: ##STR191## wherein X₁, X₂, X₃, and X₄ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR192## wherein X₂,X₃, and X₄ are independently the same or different and are H, OR, O,--OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; according to one of the suitable processes above;

and (b) coupling the compound formed in step (a) by intra-molecularcoupling under suitable conditions to form the compound having thestructure: ##STR193##

In step (a), the compound may be synthesized by the suitable processesabove or other processes determinable by those skilled in the art. Instep (b), the contacting comprises the intra-molecular Diels-Aldercoupling of the compound formed in step (a) by thermal or Lewis acidcatalyzed Diels-Alder cyclization.

The present invention further provides a process for synthesizing acompound having the structure: ##STR194## wherein X₁, X₂, and X₃ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR195## wherein X₃and X₄ is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃are the independently the same or different and are H, acyl, alkyl,aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; according to the suitable process above;

and (b) contacting the compound formed in step (a) with a compoundhaving the structure: ##STR196## wherein X₁ and X₅ are independently thesame or different and are H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂S--; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; undersuitable conditions to form the compound having the structure:##STR197##

In step (a), the compound may be synthesized by the suitable processabove or other processes determinable by those skilled in the art. Instep (b), the contacting is performed by Nozaki-Nishi (13,14) couplingof the enol triflate with the compound formed in step (a).

The present invention also provides a process for synthesizing acompound having the structure: ##STR198## wherein X₁, X₂, and X₃ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR199## wherein X₄is H, OR, O, --OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ areindependently the same or different and are H, acyl, alkyl, aryl, TBS,TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; according to the suitable process above;

and (b) contacting the compound formed in step (a) with a compoundhaving the structure: ##STR200## wherein X₁, X₂, and X₅ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and M is a metal; wherein R is H, acyl, alkyl, aryl,TBS, TES, TMS, or TBDPS; under suitable conditions to form a compoundhaving the structure: ##STR201##

In step (a), the compound may be synthesized by the suitable processabove or other processes determinable by those skilled in the art. Instep (b), the contacting is performed by nucleophilic addition of theenol to the compound formed in step (a).

The present invention also provides a process for synthesizing acompound having the structure: ##STR202## wherein X₁, X₂, X₃, and X₄ areindependently the same or different and are H, OR, O, --OCH₂ CH₂ O--, or--SCH₂ CH₂ CH₂ S--; and R₁, R₂, and R₃ are independently the same ordifferent and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; whereinR is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure: ##STR203## wherein X₁,X₂, X₃, and X₄ are independently the same or different and are H, OR, O,--OCH₂ CH₂ O--, or --SCH₂ CH₂ CH₂ S--; and R₂ and R₃ are independentlythe same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, orTBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;according to the suitable processes above;

and (b) reacting the compound formed in step (a) by reductive couplingto form the compound having the structure: ##STR204##

In step (a), the compound may be synthesized by the suitable processesabove or other processes determinable by those skilled in the art. Instep (b), the reacting is performed by reductive coupling usingsamarium(II) iodide or titanium(III) chloride.

The present invention also provides a process for synthesizing acompound having the structure: ##STR205## which comprises: (a)synthesizing a compound having the structure: ##STR206## according tothe suitable process above; (b) treating the compound formed in step (a)under suitable conditions to form a compound having the structure:##STR207## (c) contacting the compound formed in step (b) withlithiodithiane under suitable conditions to form a compound having thestructure: ##STR208## (d) deketalizing the compound formed in step (c)under suitable conditions to form a compound having the structure:##STR209## (e) contacting the compound formed in step (d) withmethoxyvinyllithium under suitable conditions to form a compound havingthe structure: ##STR210## (f) heating the compound formed in step (e)under suitable conditions to form a compound having the structure:##STR211## (g) reducing and esterifying the compound formed in step (f)under suitable conditions to form a compound having the structure:##STR212## (h) oxidizing the compound formed in step (g) under suitableconditions to form a compound having the structure: ##STR213## (i)removing the thioketal of the compound formed in step (h) under suitableconditions to form a compound having the structure: ##STR214## (j)treating the compound formed in step (i) under suitable conditions toform a compound having the structure: ##STR215## (k) treating thecompound formed in step (j) under suitable conditions to form a compoundhaving the structure: ##STR216## and (l) treating the compound formed instep (k) under suitable conditions to form the compound having thestructure: ##STR217##

In step (a), the compound may be synthesized by the suitable processabove or other processes determinable by those skilled in the art. Instep (b), the treating comprises the selective ketalization of the lesshindered aldehyde of step (a). In step (c), the contacting comprises theaddition of lithiodithiane VII followed by Swern oxidation. In step (d),the contacting comprises deketalizing the compound formed in step (c) bythe addition of acetone then PPTS. In step (e), the compound formed instep (d) is contacted with vinyllithium. In step (f), heating willcyclize the compound formed in step (e) to the tricyclic compound. Instep (g), the compound formed in step (f) is reduced by stereoselectivereduction after benzoylation of the newly generated (α) secondaryalcohol. In step (h), the compound formed in step (g) is oxidized byAllylic oxidation, followed by Swern oxidation if necessary. In step(i), the thioketal is removed by subsequent benzyl protection and Raneynickel reduction. In step (j), the treating comprises Franklin Davishydroxylation of the potassium enolate of the compound formed in step(i) to give the corresponding hydroxyketone in which the oxaziridineapproaches from the convex face. In step (k), the treating comprisesfluoride induced desilyation with TBAF, peracetylation, hydrogenolysisof the benzyl ether and subsequent side chain coupling. In step (l), thetreating comprises selectively removing the acetate at C-7, which inturn is doubly deprotected by simultaneous removal of the MOM and EEgroups to give taxol.

The following Experimental Details Section is set forth to aid in anunderstanding of the invention. This section is not intended to, andshould not be construed to, limit in any way the invention set forth inthe claims which follow thereafter.

Experimental Details Section General Procedures

All air and moisture sensitive reactions were performed in a flame-driedapparatus under an argon atmosphere unless otherwise noted. Airsensitive liquids and solutions were transferred via syringe or canula.Whenever possible, reactions were monitored by thin-layer chromatography(TLC). Gross solvent removal was performed in vacuo under aspirator on aBuchi rotary evaporator, and traces of solvent were removed on a highvacuum oil pump (0.1-0.5 mmHg).

Physical Data

Melting points (mp) were uncorrected and performed in soft glasscapillary tubes using a Electrothermal series IA9100 digital meltingpoint apparatus.

Infrared spectra (IR) were performed with a Perkin-Elmer 1600 seriesFourier-Transform (FT). Samples were prepared as neat films on NaClplates unless otherwise noted. Absorption bands are reported inwavenumbers (cm⁻¹), and are described in abbreviations: s=strong;m=medium; w=weak; br=broad. Only relevant, assignable bands arereported.

Proton nuclear magnetic resonance (¹ H NMR) spectra were determinedusing a Bruker AMX-400 spectrometer at 400 MHz. Chemical shifts arereported in parts per million (∂) downfield from tetramethylsilane (TMS:∂=0) using residual CHCl₃ as a lock reference (∂=7.25). Resonances arepresented in the following form: ∂ in ppm (multiplicity, couplingconstant=J, integral). Multiplicities are abbreviated in the usualfashion: s=singlet; d=doublet; t=triplet; q=quartet; m=multiplet; br=adescriptor for a multiplicity meaning broad.

Carbon nuclear magnetic resonance (¹³ C NMR) spectra were performed on aBruker AMX-400 spectrometer at 100 MHz with composite pulse decoupling.Samples were prepared as with ¹ H NMR and chemical shifts are reportedin ∂ relative to TMS (∂=0); the residual CHCl3 was used as an internalreference (∂=77.0).

All mass spectral analyses were performed at Columbia University at theDepartment of Chemistry. High resolution mass spectra (HRMS) weredetermined by electron impact ionization (EI) on a JEOL JMS-DX 303HFmass spectrometer with perfluorokerosene (PFK) as an internal standard.Low resolution mass spectra (MS) were determined by either electronimpact ionization (EI) or chemical ionization (CI) using the indicatedcarrier gas (NH₃ or CH₄) on a Delsi-Nermag R-10-10 mass spectrometer.For GCMS, a DB-5 fused capillary column (30 m, 0.25 m thickness) wasused with helium as the carrier gas. Typical conditions were atemperature program from 60°-250° C. at 40° C./min.

Chromatography

Thin layer chromatography (TLC) was performed using precoated glassplates (silica gel 60, 0.25 mm thickness). Visualization was done byillumination with 254 nm UV lamp, or by immersion in anisaldehyde stain(9.2 mL p-anisaldehyde in 3.5 mL HOAc, 12.5 mL concentrated H₂ SO₄ and338 mL 95% EtOH) and heating to colorization.

Flash silica gel chromatography was carried out according to theprotocol of Still (8).

Solvents and Reagents

Unless otherwise noted, all solvents and reagents were commercial gradeand were used as received from the suppliers indicated in theexperimentals. The following are exceptions, and all were distilledunder Ar using the drying methods listed in parentheses: CH₂ Cl₂ (CaH₂);PhH (CaH₂); THF (Na, PhCOPh as indicator); Et₂ O (Na, PhCOPh asindicator); diiopropylamine (CaH₂).

    ______________________________________                                        Abbreviations                                                                 ______________________________________                                        Ac            acetyl                                                          9-BBN         borobicyclo[3.3.1]nonane                                        Bu            butyl                                                           Bz            benzoyl                                                         DMSO          dimethylsulfoxide                                               DMF           dimethylformamide                                               DMP           dimethylpyrazole                                                EE            ethoxy ethyl                                                    KHMDS         potassium bis(trimethylsilyl)amide                              LDA           lithium diisopropylamide                                        MOM           methoxy methyl                                                  NMO           4-methylmorpholine N-oxide                                      Ph            phenyl                                                          PPTS          pyridinium p-toluenesulfonate                                   Pyr or Py     pyridine                                                        TBAF          tetrabutylammonium fluoride                                     TBS or TBDMS  tert-butyldimethylsilyl                                         TBDPS         tert-butyldiphenylsilyl                                         TES           triethylsilyl                                                   THF           tetrahydrofuran                                                 TLC           thin-layer chromatography                                       TMS           trimethylsilyl                                                  Tf            trifluoromethane sulfonate                                      ______________________________________                                    

Route 1 Synthesis Preparation of enol triflate 2

A solution of potassium bis(trimethylsilyl)amide (KHMDS, 12.9 g, 64.7mmol, 1.5 eq) in tetrahydrofuran (anhydrous, 200 mL) was cooled to 0° C.under nitrogen using an ice-bath and was stirred for 15 minutes. To thissolution was added dropwise a solution of the known ketoketal 1 (9)(8.546 g, 43.16 mmol, 1.0 eq) in tetrahydrofuran (50 mL) and the mixturewas stirred for 2 hours at 0° C. until no more precipitate appeared.Then N-phenyl trifluoromethanesulfonimide (PhNTf₂, 25 g, 70 mmol, 1.62eq) was added portionwise giving immediately a pale brown homogeneoussolution. TLC (ethyl acetate/hexanes, 1:4) showed total disappearance ofthe starting ketoketal and formation of a slightly less polar product aswell as N-phenyl trifluoromethanesulfonamide (PhNHTf), the by productderived from the imide. The solution was then warmed to roomtemperature, diluted with ether (200 mL) and washed with brine (2×100mL). The aqueous layers were combined and washed with ether (2×200 mL)and the combined organic layers were dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was chromatographed (600mL of silica gel, 40-65μ, dichloromethane/hexanes, 1:3) to give 11.73 g(82.4%) of the triflate 2 as a pale yellow oil.

¹ H NMR (CDCl₃, 400 MHz): ∂3.99 (s, 4H), 2.22 (brt, J=6.5 Hz, 2H), 1.80(brt, J=6.5 Hz, 2H), 1.78 (s, 3H), 1.18 (s, 6H).

¹³ C NMR, CDCl₃, ∂17.42, 20.88, 26.56, 28.11, 44.48, 65.26, 111.42,113.93, 117.10, 120.28, 123.45, 125.27, 146.77.

HRMS calcd. for C₁₂ H₁₇ O₅ F₃ S: 330.0749; found: 330.0735.

MS 41(38), 55(35), 69(30), 86(100), 165(56), 180(27), 330(10), 93(38),99(41), 107(37), 137(25).

IR (neat, thin film, cm⁻¹) 2989.1, 2950.8, 2888.5, 1689.9, 1471.2,1454.6, 1402.3.

R_(f) =0.56 (ethyl acetate/hexanes, 3:7).

Preparation of diene 3

To a solution of triflate 2 (8.43 g, 25.54 mmol, 1 eq),vinyltributylstannane (12.15 g, 11.2 mL, 38.32 mmol, 1.5 eq) and lithiumchloride (anhydrous, 3.25 g, 76.64 mmol, 3 eq) in tetrahydrofuran(anhydrous, 150 mL) was added tetrakis(triphenylphosphine)palladium(O)(Pd(PPh₃)₄, 1.48 g, 1.28 mmol, 5 mol %) and the green mixture wasrefluxed for 24 hours. The mixture was then cooled to room temperature.Work up A: the mixture was diluted with ethyl acetate (50 mL) and washedwith brine (2×100 mL). The aqueous layers were combined and extractedwith ethyl acetate (3×50 mL) and the combined organic layers were driedover magnesium sulfate, filtered, concentrated under vacuum and purifiedby two successive silica gel chromatographies (each time 500 mL ofsilica gel, 40-65μ, ether/hexanes, 5:95) to give 4.85 g (91.4%) of thediene 3 as a pale yellow oil. To avoid the second chromatography due tothe presence of a large quantity of chlorotributylstannane, basictreatment was employed: work up B: the majority of the by-product wasremoved by adding 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.5 eq) aftercooling the mixture to room temperature. It was then diluted with ether(600 mL) and washed with 1N sodium hydroxide (3×150 mL), brine (200 mL),dried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was triturated with ether (3×100 mL) and the combined etherallayers were concentrated in vacuo and found to be devoid of tinby-products. Flash chromatography (same conditions) gave similar yieldof diene 3.

¹ H NMR (CDCl₃, 400 MHz): ∂6.15 (m, 1H), 5.27 (dd, J=11.2, 2.6 Hz, 1H),4.99 (dd, J=17.6, 2.6 Hz, 1H), 2.18 (m, 2H), 1.78 (t, J=6.7, 2H), 1.71(d, J=0.9 Hz, 3H), 1.05 (s, 6H).

¹³ C NMR, CDCl₃, ∂20.92, 22.87, 26.70, 30.67, 42.04, 64.94, 112.08,118.78, 126.98, 135.02, 137.46.

IR (neat, thin film, cm⁻¹) 3078.0, 2976.0, 2878.7, 1621.5, 1469.8,1451.7.

HRMS calcd. for C₁₃ H₂₀ O₂ : 208.1463; found 208.1459.

MS 41(35), 55(30), 86(30), 87(40), 107(100), 122(28), 208(51).

R_(f) =0.45 (ethyl acetate/hexanes 1:4).

Preparation of alcohol 4

A three-necked 500 mL flask was charged with a solution of the diene 3(23 mmol, 4.79 g) in anhydrous tetrahydrofuran (25 mL), and then with a9-borabicyclo[3.3.1]nonane (9-BBN, 0.5M solution in tetrahydrofuran,138.2 mL, 69.1 mmol, 3 eq) and the mixture was immediately refluxed for1.5 hours. TLC (ethyl acetate/hexanes, 1:1) showed total disappearanceof the starting material. The mixture was then cooled to roomtemperature and ethanol (40 mL) was added, followed by 6N sodiumhydroxide (15 mL), then dropwise 30% hydrogen peroxide (28 mL),maintaining a gentle reflux. After one hour, the mixture had cooled toroom temperature, diluted with ether (100 mL) and washed with brine(2×200 mL). The aqueous layers were back extracted with ether (3×100 mL)and the combined organic layers were dried over magnesium sulfate,filtered and evaporated. Flash chromatography of the residue (silicagel, 40-65μ, 600 mL, ethyl acetate/hexanes, 1:5, then 1:4, then 1:3,then 1:2) gave pure alcohol 4 (4.886 g, 93.9%) as a pale yellow oil.

¹ H NMR (CDCl₃, 400 MHz): ∂3.947-3.99 (m, 4H), 3.609 (t, J=8 Hz, 2H),3.609 (t, J=8 Hz, 2H), 2.345 (t, J=8 Hz, 2H), 2.108 (t, J=6.6 Hz, 2H),1.747 (t, J=6.7 Hz, 2H), 1.677 (s, 3H), 1.058 (s, 6H).

¹³ C NMR, CDCl₃, ∂19.82, 22.72, 26.68, 30.60, 32.36, 40.09, 62.27,64.84, 112.21, 128.43, 132.05.

IR (neat, thin film, cm⁻¹) 3471.5, 2953.2, 2882.3, 1477.1, 1379.6,1355.5, 1208.4, 1140.6, 1089.2, 1056.0, 949.7, 906.2.

HRMS Calcd. for C₁₃ H₂₂ O₃ : 226.1569; found: 226.1568.

MS 43(76), 55(39), 86(100), 87(75), 97(28), 107(28), 125(26), 196(20),226(15).

R_(f) =0.43 (ethyl acetate:hexanes, 1:1).

Preparation of aldehyde 5

A 50 mL round bottom flask was charged with 5 mL of dichloromethane and1 mL of a 2M solution of oxalyl chloride in dichloromethane (2 mmol, 2eq), and the solution was cooled to -60° C. To this cooled solution wasadded dropwise dimethylsulfoxide (0.71 mL, 781 mg, 10 mmol, 5 eq) andthe mixture was stirred 15 minutes at -60° C. A solution of the alcohol4 (226 mg, 1 mmol, 1 eq) in dichloromethane (2 mL) was added dropwise,and the mixture was stirred at -60° C. for 15 minutes. Triethylamine(1.4 mL, 1.012 g, 10 mmol, 5 eq) was added and the mixture was allowedto warm to room temperature before being diluted with water (10 mL) andether (10 mL). The aqueous phase was extracted with ether (10 mL) andthe combined organic layers were washed with 0.1N hydrochloric acid (10mL), then brine (10 mL), dried over magnesium sulfate, filtered andevaporated. Flash chromatography of the residue (silica gel, 40-65μ, 100mL, ether/hexanes 15:85) gave pure aldehyde 5 (210 mg) in 93.7% yield,as a pale yellow oil.

¹ H NMR (CDCl₃, 400 MHz): ∂9.535 (t, J=2.4 Hz, 1H), 3.948-4.031 (m, 4H),3.116 (brs, 2H), 2.213 (t, J=6.6 Hz, 2H), 1.792 (t, J=6.6 Hz, 2H), 1.622(s, 3H), 1.032 (s, 6H)

¹³ C NMR, CDCl₃, ∂19.72, 22.38, 26.57, 30.70, 43.87, 64.79, 111.67,127.80, 131.18, 200.65.

IR (neat, thin film, cm⁻¹) 2883.1, 2717.3, 1722.1, 1472.2, 1427.2,1380.5, 1357.1, 1327.3, 1306.4, 1208.5, 1141.0, 1086.7, 1056.4, 991.4,949.9, 906.2.

HRMS Calcd. for C₁₃ H₂₀ O₃ : 224.1412; found: 224.1393.

MS 41(26), 73(20), 86(85), 87(100), 95(18), 224(48).

R_(f) =0.75 (ethyl acetate/hexanes, 1:1).

Preparation of alcohol 6

A dry 100 mL flask equipped with stir bar was charged with a solution ofaldehyde 5 (1.0 gm; 4.5 mmol) in tetrahydrofuran (25 mL). The solutionwas cooled to 0° C., and a solution of the grignard reagent derived from2-bromopropene (0.64M in tetrahydrofuran; 7.7 mL, 1.1 eq.) was addeddropwise over 5 minutes. When the addition was complete the mixture wasstirred at 0° C. an additional 30 minutes and then at room temperaturefor 30 minutes. TLC (ethyl acetate/hexanes, 1:5) indicated that all thestarting aldehyde (r_(f) =0.27) had been consumed, and showed theappearance of a new product (r_(f) =0.14). Saturated ammonium chloride(40 mL) was added, and the mixture partitioned between ethyl acetate(100 mL) and water (100 mL). The aqueous phase was decanted and theorganic phase washed with brine (2×100 mL), dried over anhydrousmagnesium sulfate, filtered and the filtrate concentrated in vacuo.Purification of the residue by flash chromatography (150 mL of silicagel eluted with ethyl acetate/hexanes, 1:5) gave the allylic alcohol 6(1.1 gm; 4.0 mmol; 89%) as a pale yellow oil.

¹ H NMR (CDCl₃, 400 MHz): ∂5.00 (brs, 1H), 4.81 (brs, 1H), 4.22 (dd,J=10.2, 3.6 Hz, 1H), 3.92-4.02 (m, 4H), 2.42 (dd, J=14.2, 10.2 Hz, 1H),2.08-2.32 (m, 4H), 1.80 (s, 3H), 1.73-1.88 (m, 2H), 1.72 (s, 3H), 1.11(s, 3H), 1.10 (s, 3H).

¹³ C NMR, CDCl₃ , ∂17.87, 20.59, 22.73, 22.61, 29.60, 30.79, 35.25,43.18, 64.89, 74.45, 109.88, 112.31, 130.62, 132.34, 147.71.

IR (neat, thin film, cm⁻¹) 3454.0, 2926.6, 1715.5, 1651.5, 1452.9,1379.0, 1356.2, 1209.6, 1134.3, 1088.0, 1058.4, 991.6, 901.6.

HRMS Calcd for C₁₆ H₂₆ O₃ : 266.1882; found: 266.1886.

MS 87(70), 99(46), 109(23), 168(28), 196(45), 205(24), 235(18),249(100), 266(4), 267(34).

R_(f) =0.43 (ethyl acetate/hexanes, 1:1).

Preparation of enone 7

A 2M solution of oxalyl chloride in dichloromethane (170 μL, 0.34 mmol,2 eq) in 1 mL of anhydrous dichloromethane were cooled under nitrogen to-60° C. Dimethylsulfoxide (71 μl, 6 eq) was added, and after 15 minutes,a solution of the alcohol 6 (45 mg, 0.17 mmol, 1 eq) in dichloromethane(1 mL). After 30 minutes, triethylamine (0.5 mL, excess) was added, andthe mixture was allowed to warm to room temperature. It was then dilutedwith ether and water (5 mL each) and the etheral layer was washed with0.1N hydrochloric acid (10 mL). The aqueous phase was then extractedwith ether (2×5 mL) and the combined organic layers were washed withbrine, dried over magnesium sulfate, filtered, and evaporated. Flashchromatography of the residue (100 mL of silica gel, 40-65μ, ethylacetate/hexanes, 1:4) gave 43 mg (96%) of the enone 7 as a pale yellowoil.

¹ H NMR (CDCl₃, 400 MHz): ∂6.00 (brs, 1H), 5.74 (brs, 1H), 3.92-4.02 (m,4H), 3.47 (brs, 2H), 2.20 (brt, J=6.4 Hz, 2H), 1.89 (s, 3H), 1.79 (t,J=6.6 Hz, 2H), 1.49 (s, 3H), 0.97 (s, 6H).

¹³ C NMR, CDCl₃, ∂17.94, 20.10, 22.53, 26.76, 30.55, 37.07, 42.98,64.88, 112.09, 123.27, 129.68, 130.07, 144.82, 199.04.

IR (neat, thin film, cm⁻¹) 2926.5, 1686.1, 1452.0, 1336.0, 1208.5,1130.1, 1088.6, 1063.6, 902.4.

HRMS Calcd for C₁₆ H₂₄ O₃ : 264.1725; found: 264.1719.

MS 69(85), 86(100), 87(51), 99(25), 109(30), 135(25), 150(23), 163(18),178(24), 221(16), 264(32).

R_(f) =0.65 (ethyl acetate/hexanes, 1:1).

Preparation of adduct 8

A solution of enone 7 (28 mg, 0.106 mmol) and diene (0.424 mmol, 4 eq)in deuterated benzene (0.5 mL) was added into a base washed sealable NMRtube. The extent of the reaction was monitored by studying thedisappearance of the starting enone by NMR of the whole mixture. After2.5 days at 125° C., the pale brown solution did not contain any morestarting material and showed a 2:1 ratio of 2 products. The mixture wasevaporated to dryness and treated with a 0.1N hydrochloricacid/tetrahydrofuran mixture (1 mL, 1:4 vol) and stirred at roomtemperature for 30 minutes. The mixture was then poured into a saturatedhydrogenocarbonate solution (5 mL) and extracted with dichloromethane(3×10 mL). The combined organic layers were dried over magnesiumsulfate, filtered and evaporated. Flash chromatography of the residue(100 mL of silica gel, ethyl acetate/hexanes, 1:2) gave 28.5 mg of enone8 (81%) as a pale yellow oil.

¹ H NMR (CDCl₃, 400 MHz): ∂7.02 (dd, J=10.2, 1.05 Hz, 1H), 6.05 (d,J=10.2 Hz, 1H), 3.92-4.02 (m, 4H), 3.31 (s, 2H), 2.54 (m, 1H), 2.43 (m,2H), 2.20 (t, J=6.6 Hz, 2H), 1.91 (m, 1H), 1.78 (t, J=6.6 Hz, 2H), 1.43(s, 3H), 1.42 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H).

¹³ C NMR, CDCl₃, ∂15.24, 19.96, 22.52, 25.24, 26.68, 30.54, 32.63,34.79, 38.83, 42.80, 49.95, 64.91, 111.85, 128.60, 129.21, 130.44,152.24, 198.43, 206.76.

IR (neat, thin film, cm⁻¹) 2924.4, 1716.1, 1679.9, 1604.4, 1456.1,1356.7, 1270.8, 1088.8, 1057.2.

MS 41(18), 55(19), 67(19), 79(22), 81(41), 86(100), 87(53), 109(80),110(93), 121(40), 137(70), 195(32), 223(40), 289(23), 332(92).

HRMS Calcd for C₂₀ H₂₈ O₄ : 332.1988; found: 332.1960.

R_(f) =0.36 (ethyl acetate/hexanes 1:1).

Preparation of trione 9

The ketal 8 (183 mg, 0.55 mmol) was stirred 3 hours at 45° C. in 4 mL ofa 1:1 vol mixture of tetrahydrofuran and water in presence ofp-toluenesulfonic acid (104 mg, 0.55 mmol). NMR analysis of aliquotsallowed monitoring of the reaction. After three hours, all the startingketal has disappeared. The mixture was then diluted with ether (20 mL),washed with sodium hydrogenocarbonate (sat., 20 mL). The aqueous layerwas extracted with ether (20 mL) and the combined organic layers werewashed with brine (20 mL), dried over magnesium sulfate, filtered andevaporated, to give pure deketelized product 9 (141.4 mg, 89.1%), as acolorless oil.

¹ H NMR (CDCl₃, 400 MHz): ∂7.04 (dd, J=10.2, 1.2 Hz, 1H), 6.08 (d,J=10.2 Hz, 1H), 3.36 (brs, 2H), 2.50-2.63 (m, 3H), 2.40-2.49 (m, 4H),1.96 (ddd, J=10.5, 13.2, 5.2 Hz, 1H), 1.53 (s, 3H), 1.53 (s, 3H), 1.45(s, 3H), 1.054 (s, 3H), 1.047 (s, 3H).

¹³ C NMR, CDCl₃, ∂20.00, 24.13, 24.16, 25.06, 31.38, 32.47, 34.62,35.80, 38.76, 47.28, 49.87, 128.61, 129.30, 131.64, 151.79, 198.07,206.62, 214.11.

IR (thin film, cm⁻¹) 2968.8, 2927.7, 2871.4, 1712.6, 1682.7, 1605.6,1463.4, 1415.0, 1377.7, 1323.2, 1228.6, 1091.9, 1032.7, 1018.5, 807.1.

MS 41(28), 43(19), 53(20), 55(18), 67(17), 79(19), 81(50), 110(100),123(53), 136(5), 151(8), 288(20).

HRMS Calcd for C₁₈ H₂₄ O₃ : 288.1725; found: 288.1716.

R_(f) =0.36 (ethyl acetate/hexanes 1:1).

Preparation of Compound 10

To a solution of enone 9 (45 mg, 0.156 mmol) in benzene (anhydrous 2 mL)was added dropwise at room temperature 1.1 mL of a 1M solution ofdiethylaluminium cyanide in toluene (7 eq). After 10 minutes at roomtemperature, 1N sodium hydroxide was added (5 mL) and the mixture wasstirred vigorously. Dichloromethane (5 mL) was added, and the aqueousphase was extracted with more dichloromethane (5 mL). The combinedlayers were washed with brine (10 mL), dried over magnesium sulfate,filtered and evaporated. Crude NMR showed a 3:1 ratio of 2 products aswell as a small amount of remaining starting enone 9. Flashchromatography of the residue (50 mL of silica gel, 40-65μ, ethylacetate/hexanes, 1:4-1:2) gave 3 fractions; starting enone 9 (9 mg,20%), and two cyanides, trans (9 mg, 19%) and cis (28 mg, 57%) bycomparison to the methyl group. Based on starting material recovery, theyield of cyanides products is 96%.

¹ H NMR (CDCl₃, 400 MHz): ∂3.50 (d, J=19.1 Hz, 1H--AB system), 3.36 (d,J=19.1 Hz, 1H--AB system), 3.06 (dd, J=15, 10 Hz, 1H), 2.99 (dd, J=10,4.6, 1H), 2.68 (dd, J=15, 4.6 Hz, 1H), 2.61 (t, J=6.7 Hz, 2H), 2.42-2.51(m, 4H), 2.30-2.40 (m, 1H), 1.93-2.06 (m, 1H), 1.61 (s, 3H), 1.59 (s,3H), 1.09 (s, 3H), 1.08 (s, 3H).

¹³ C NMR, CDCl₃, ∂20.16, 23.74, 24.22, 24.37, 31.47, 33.01, 35.88,36.89, 37.12, 37.24, 40.04, 47.34, 49.39, 118.72, 128.08, 132.32,204.35, 207.14, 213.96.

IR (neat, thin film, cm⁻¹) 2969.8, 2925.0, 2240.5, 1712.2, 1465.0,1418.8, 1319.3, 1091.9, 1031.6, 1018.9, 916.1, 732.8.

MS 109(4), 123(9), 179(10), 273(15), 299(13), 315(27), 316(100), 317(17).

HRMS Calcd. for C₁₉ H₂₅ O₃ N: 315.1835; found: 315.1818.

R_(f) =0.18 (ethyl acetate/hexanes 1:1) (trans isomer of 10: 0.38)

Preparation of hydroxy enone 11

To a solution of potassium bis(trimethylsilyl)amide (KHMDS, 66 mg, 0.33mmol, 3 eq) in tetrahydrofuran (anhydrous, 2 mL) cooled to -78° C. undernitrogen, was added a solution of the enone 7 (29 mg, 0.11 mmol, 1 eq)in tetrahydrofuran (3 mL). After 15 minutes, a solution ofN-phenylsulfonyl phenyloxaziridine (86 mg, 0.33 mmol, 3 eq) was added tothe green solution which was then decolored. The reaction was stirred 30minutes at -78° C. before being quenched with saturated solution ofammonium chloride (2 mL) and warmed to room temperature. The mixture wasdiluted with ether (10 mL) washed with brine (10 mL), dried overmagnesium sulfate, filtered and concentrated under reduce pressure.Flash chromatography of the residue (100 mL silica gel, 40-65μ, ethylacetate/hexanes, 1:2) gave 26.7 mg of the hydroxyenone 11 (87%).

¹ H NMR (CDCl₃, 400 MHz): ∂6.07 (s, 1H), 5.77 (brs, 1H), 5.08 (s, 1H),4.15 (brs, 1H), 3.89-4.00 (m, 4H), 2.19 (t, J=6.6 Hz, 2H), 1.96 (d,J=0.7 Hz, 3H), 1.68-1.86 (m, 2H), 1.63 (s, 3H), 1.21 (s, 3H), 1.05 (s,3H).

¹³ C NMR, CDCl₃, ∂18.83, 20.23, 22.98, 23.95, 26.54, 31.62, 43.74,65.01, 74.56, 111.82, 125.95, 133.68, 135.87, 141.43, 204.31.

IR (neat, thin film, cm⁻¹) 3447.1, 2884.8, 1664.0, 1067.4, 1571.0,1451.4, 1376.5, 1298.2, 1208.8, 1162.5, 1136.6, 1087.3, 1058.9, 1034.0,949.5.

MS 41(100), 43(32), 69(32), 86(58), 107(100), 121(70), 149(43), 167(35),211(82), 252(3), 280(20).

HRMS Calcd for C₁₆ H₂₄ O₄ : 280.1675; found: 280.1676.

R_(f) =0.54 (ethyl acetate/hexanes, 1:1).

Preparation of compound 12

The glassware was washed with 1N sodium hydroxide, distilled water, andwas then dried in the oven (140° C.). A sealable NMR tube containing amixture of the enone 11 (23 mg, 0.082 mmol) and1-methoxy-3-trimethylsilyloxy-1,3-butadiene (0.424 mmol, 5.2 eq) in asolution of deuterated benzene was heated 3 hours at 140° C. NMRanalysis showed total disappearance of the starting enone, but noevidence of any Diels-Alder adducts were found in the spectrum. Themixture was then directly applied to a column of silica gel (50 mL,silica gel, 40-65μ, ethyl acetate/hexanes, 1:4) and eluted with the samesolvent to give 23 mg (80%) of enone 12 as a pale yellow oil.

¹ H NMR (CDCl₃, 400 MHz): ∂5.07 (m, 1H), 5.05 (m, 1H), 4.74 (s, 1H),3.92-4.03 (m, 4H), 2.11-2.27 (m, 2H), 1.75-1.92 (m, 2H), 1.79 (s, 3H),1.61 (s, 3H), 1.21 (s, 3H), 1.035 (s, 3H), 0.14 (s, 9H).

¹³ C NMR, CDCl₃, ∂0.03, 18.05, 21.33, 22.52, 24.53, 26.69, 30.37, 41.28,65.13, 83.28, 111.43, 115.79, 130.44, 130.87, 143.02, 207.40.

IR (neat, thin film, cm⁻¹) 2955.9, 1694.8, 1250.4, 1101.9, 889.0, 842.7.

MS 73(8), 87(9), 137(19), 181(22), 209(100), 307(6), 352(2).

HRMS Calcd for C₁₉ H₃₂ O₄ Si: 352.2070; found: 352.2051.

R_(f) =0.71 (ethyl acetate/hexanes, 1:1).

Preparation of Compound 13

Dichloromethane (anhydrous, 2 mL) and oxalyl chloride (0.35 mL of a 2Msolution in dichloromethane, 0.7 mmol, 2.3 eq) were cooled undernitrogen at -60° C. Dimethylsulfoxide (0.15 mL, 2.14 mmol, 7 eq) wasthen added slowly and after 15 minutes, a solution of the alcohol 11 (85mg, 0.3 mmol, 1 eq in dichloromethane, 2 mL). After 30 minutes at-60°--50° C., triethylamine (1 ml, excess) was added, and the mixturewas allowed to warm to room temperature. Ether (10 mL) and water (10 mL)were added and the organic phase was washed with 0.1N hydrochloric acid(10 mL). The aqueous layers were combined and extracted with ether (2×10mL). The combined organic layers were washed with brine (20 mL), driedover magnesium sulfate, filtered and concentrated under reducedpressure. Flash chromatography of the residue (50 mL silica gel, 40-65μ,ethyl acetate/hexanes 1:4) gave the dione 13 (58 mg, 69%) as a yellowoil.

¹ H NMR (CDCl₃, 400 MHz): ∂6.20 (m, 1H), 6.10 (dq, J=0.7, 0.9 Hz, 1H),3.95-4.02 (m, 4H), 2.30 (brt, J=6.7 Hz, 2H), 1.94 (dd, J=1.4, 0.9 Hz,3H), 1.82 (t, J=6.7 Hz, 2H), 1.67 (s, 3H), 1.18 (s, 6H).

¹³ C NMR, CDCl₃, ∂17.18, 21.40, 22.88, 26.34, 31.67, 42.07, 65.10,111.17, 131.23, 138.44, 139.54, 139.68, 193.76, 197.76.

IR (neat, thin film, cm⁻¹) 2980.0, 2957.7, 2883.8, 1668.7, 1454.4,1378.0, 1259.9, 1213.0, 1137.4, 1110.6, 1042.9.

MS 41(88), 43(28), 45(30), 67(32), 69(30), 87(29), 137(50), 181(30),209(100), 278(18).

HRMS Calcd for C₁₆ H₂₂ O₄ : 278.1518; found: 278.1515.

R_(f) =0.58 (ethyl acetate/hexanes 1:1).

Preparation of adduct 14

In a base washed NMR tube with a screwable teflon joint, a solution ofenone 13 (48 mg, 0.172 mmol) and diene (0.69 mmol, 4 eq) in deuteratedbenzene (0.5 mL) was heated at 80° C. After 3 hours, NMR analysis showedthat the reaction was complete. The solvent was evaporated and theresidue was treated with 0.1N hydrochloric acid/tetrahydrofuran (2 mL,1:4 vol) for 30 minutes. The mixture was then poured into a saturatedsolution of sodium hydrogenocarbonate (20 mL) and extracted withdichloromethane (2×20 mL). The combined organic layers were dried overmagnesium sulfate, filtered and evaporated to give enone 14 as a yellowoil (crude 95%) which showed satisfactory purity (NMR).

¹ H NMR (CDCl₃, 400 MHz): ∂7.27 (dd, J=10.2, 1.2 Hz, 1H), 6.00 (d,J=10.2 Hz, 1H), 3.92-4.02 (m, 4H), 2.60 (m, 1H), 2.46 (m, 2H), 2.25 (m,2H), 1.97 (dt, J=13.6, 8, 8 Hz, 1H), 1.82 (m, 2H), 1.55 (s, 3H), 1.47(s, 3H), 1.09 (s, 3H), 1.03 (s, 3H).

¹³ C NMR, CDCl₃, ∂20.92, 22.25, 23.38, 25.22, 26.34, 30.66, 32.59,34.38, 42.01, 47.98, 65.06, 65.11, 110.75, 129.32, 135.73, 136.37,151.04, 196.32, 197.91, 198.14.

IR (neat, thin film, cm⁻¹) 2922.9, 2852.6, 1684.9, 1456.0, 1380.1,1228.1, 1137.1, 1103.1, 1049.1, 992.3, 825.2.

MS 41(20), 55(25), 67(28), 81(27), 86(23), 87(25), 95(20), 137(40),181(28), 209(100), 346(18).

HRMS Calcd for C₂₀ H₂₆ O₅ : 346.1780; found: 346.1792.

R_(f) =0.40 (ethyl acetate/hexanes, 1:1).

Preparation of Compound 15

The ketal 14 (56 mg, 0.16 mmol) was treated with p-toluenesulfonic acid(30 mg, 0.16 mmol) at 60° C. for 21 hours in a tetrahydrofuran/watermixture (1:1 vol, 2 mL) and the reaction was monitored by NMR analysisof aliquots. The mixture was then diluted with ether (10 mL) and pouredinto saturated hydrogenocarbonate (5 mL). The aqueous layer wasextracted with ether (10 mL) and the combined organic layers were washedwith brine (10 mL), dried over magnesium sulfate, filtered andevaporated. Flash chromatography of the residue (50 mL of silica gel40-65μ, ethyl acetate/hexanes 1:4) gave 2 fractions, remaining startingketal (5 mg) and tetraone 15 (35.4 mg, 0.117 mmol, 73.3%, 79.4% based onstarting material recovery), as a yellow oil.

¹ H NMR (CDCl₃, 400 MHz): ∂7.25 (dd, J=10.2, 1.1 Hz, 1H), 6.04 (d,J=10.2 Hz, 1H), 2.58-2.68 (m, 3H), 2.40-2.57 (m, 4H), 2.02 (ddd, J=13.4,10, 5.7 Hz, 1H), 1.60 (s, 3H), 1.58 (s, 3H), 1.23 (s, 3H), 1.17 (s, 3H).

¹³ C NMR, CDCl₃, ∂21.47, 24.07, 25.02, 25.18, 31.29, 32.51, 34.34,34.97, 46.07, 48.02, 129.61, 135.77, 138.37, 150.64, 195.04, 197.90,198.13, 211.80.

IR (thin film, cm⁻¹) 2971.6, 2930.1, 1680-1720, 1461.8, 1379.4, 1230.8,1210.1, 1127.0, 1033.7, 874.5, 827.8, 803.6.

MS (CH₄) 165(100), 303(79), 304(20).

HRMS. Calcd for C₁₈ H₂₂ O₄ : 302.1518; Calcd for M+H (C₁₈ H₂₃ O₄):303.1596. found: 303.1586.

R_(f) =0.44 (ethyl acetate/hexanes, 1:1).

Preparation of Compound 16

A 25 mL flask was charged with a solution of the alcohol 4 (226 mg, 1mmol) in dichloromethane (5 ml), triethylamine (anhydrous, 121 mg, 1.2eq), 4-dimethylaminopyridine (12 mg, 0.1 eq), and the mixture was cooledto 0° C. under nitrogen. A solution of t-butylchlorodimethylsilane (166mg, 1.1 eq) in dichloromethane (3 mL) was added, and the mixture wasstirred for 1 hour at room temperature and was then washed with 5%sodium hydrogenocarbonate (10 mL) and brine (10 mL). The aqueous layerswere extracted with dichloromethane (10 mL) and the combined organiclayers were dried over magnesium sulfate, filtered, and evaporated.Flash chromatography of the residue (100 mL, silica gel, 40-65μ, 5%ether in hexanes) gave 16 (280 mg, 76% yield) as a clear oil.

¹ H NMR (CDCl₃, 400 MHz): ∂3.94-4.05 (m, 4H), 3.61 (t, J=8.5 Hz, 2H),2.33 (t, J=8.5 Hz, 2H), 2.12 (t, J=6.6 Hz, 2H), 1.76 (t, J=6.6 Hz, 2H),1.69 (s, 3H), 1.08 (s, 6H), 0.93 (s, 9H), 0.09 (s, 6H).

¹³ C NMR, CDCl₃, ∂-5.21, 18.32, 19.76, 22.60, 25.98, 26.67, 30.55,32.87, 43.05, 62.74, 64.83, 112.11, 127.80, 132.44.

HRMS Calcd for C₁₉ H₃₆ O₃ Si: 340.2434; found: 340.2447.

MS 73(50), 75(53), 86(50), 165(95), 197(100), 239(27), 283(25), 297(12),325(10), 340(13).

IR (neat, thin film, cm⁻¹) 2952.9, 1253.8, 1079.1, 835.5, 774.4.

R_(f) =0.59 (ethyl acetate/hexanes 1:4).

Preparation of enone 17

Chromium trioxide (275 mg, 2.76 mmol, 20 eq) was suspended in anhydrousdichloromethane (4 mL) and cooled to -23° C. (carbon tetrachloride/solidcarbon dioxide bath). After 10 minutes, 3,5-dimethylpyrazole (265 mg,2.76 mmol, 20 eq) was added in one portion. The suspension then became ared-brown solution. After 20 minutes of stirring at -23° C., a solutionof the olefin 16 (47 mg, 0.13 mmol, 1 eq) in dichloromethane (3 mL) wasadded and the mixture was then stirred one hour between -20° and -10° C.Sodium hydroxide of (6N, 1 mL) was added and the mixture was stirred 30minutes at 0° C. After dilution with water and dichloromethane, theaqueous phase was re-extracted with dichloromethane (5 mL) and thecombined organic layers were washed with 0.1N hydrochloric acid, thenbrine, and were then dried over magnesium sulfate. Filtration,evaporation, and flash chromatography (60 mL, silica gel, 40-65μ, ethylacetate/hexanes 1:4) gave 23.3 mg (48%) of enone 17 as a pale yellowoil.

¹ H NMR (CDCl₃, 400 MHz): ∂3.93-4.03 (m, 4H), 3.71 (t, J=8 Hz, 2H), 2.74(s, 2H), 2.61 (t, J=8 Hz, 2H), 1.85 (s, 3H), 1.24 (s, 6H), 0.92 (s, 9H),0.09 (s, 6H).

¹³ C NMR, CDCl₃, ∂-5.29, 11.94, 18.28, 21.72, 25.90, 34.52, 43.93,45.78, 61.26, 65.23, 111.71, 131.73, 159.03, 196.57.

IR (neat, thin film, cm⁻¹) 2928.0, 2881.6, 2856.1, 1673.3, 1611.4,1471.7, 1335.1, 1252.3, 1130.9, 1073.7, 836.1, 776.5.

MS 43(26), 73(73), 75(70), 89(46), 179(78), 253(49), 268(100), 297(20),354(4), 355(18).

HRMS Calcd for C₁₉ H₃₄ O₄ Si: 354.2227; found: 354.2225.

R_(f) =0.23 (ethyl acetate/hexanes, 1:4).

Preparation of Compound 18

The enone 17 (5.4 mg, 0.0153 mmol) was stirred in acetone (1 mL) in thepresence of p-toluenesulfonic acid (19 mg, 0.1 mmol) and water (50 μl).After 4 hours at room temperature, TLC showed that all the startingmaterial has disappeared. The mixture was then diluted with 2 mL ofether, washed with 2 mL of saturated aqueous solution of sodiumhydrogenocarbonate. The organic phase was then washed with 2 mL ofbrine, dried over magnesium sulfate filtered and evaporated to givealcohol 18 (3 mg, 82%).

¹ H NMR (CDCl₃, 400 MHz): ∂3.92-4.02 (m, 4H), 3.77 (t, J=7.8 Hz, 2H),2.73 (s, 2H), 2.65 (t, J=7.8 Hz, 2H), 1.85 (s, 3H), 1.24 (s, 6H).

MS (CH₄) 87(58), 179(50), 211(20), 223(22), 241(M+1, 100), 269(M+1+28,24), 281(M+1+40, 11).

HRMS Calcd for C₁₃ H₂₀ O₄ : 240.1362; found: 240.1382.

Preparation of Compound 19

Heating the ketal 4 (44 mg, 0.195 mmol) in 2 mL of a 1:1 (vol) mixtureof water and tetrahydrofuran at 45° C. gave, after dilution with ether,washing with saturated sodium hydrogenocarbonate then brine, drying overmagnesium sulfate, filtration and evaporation, the pure ketone 19 as acolorless oil. TLC did not allow monitoring of the outcome of thereaction. NMR analysis of aliquots indicated that 2 hours weresufficient for completion of the hydrolysis which was quantitative.

¹ H NMR (CDCl₃, 400 MHz): ∂3.64 (t, J=8.1 Hz, 2H), 2.53 (t, J=7 Hz, 2H),2.40 (t, J=8.1 Hz, 2H), 2.35 (t, J=7 Hz, 2H), 2.08 (brs, 1H), 1.76 (s,3H), 1.18 (s, 6H).

¹³ C NMR, CDCl₃, ∂19.87, 24.54, 31.57, 32.45, 35.93, 47.82, 62.16,129.70, 132.48, 215.34.

IR (neat, thin film, cm⁻¹) 3409.7, 2969.5, 2929.3, 1712.2, 1471.1,1446.0, 1378.3, 1357.6, 1039.5.

MS 41(45), 55(40), 81(56), 96(42), 107(44), 124(100), 137(18), 149(20),182(30).

HR Calcd for C₁₁ H₁₈ O₂ : 182.1307; found: 182.1318.

R_(f) =0.43 (ethyl acetate/hexanes 1:1).

Preparation of diol 20

A solution of the diene 3 (214 mg, 1.03 mmol) andN-methylmorpholine-N-oxide (NMO, 127 mg, 1.08 mmol, 1.05 eq) was stirredin an acetone-water mixture (8:1 vol, 5 mL) while bubbling nitrogenthrough the solution. Then a 0.1M solution of osmium tetroxide int-butanol (1 mL, 0.1 mmol, 0.097 eq) was added and stirring and nitrogenbubbling was continued 3 hours until TLC (ethyl acetate/hexanes, 1:1vol) showed total disappearance of the starting diene leading to a muchmore polar product. The reaction was then quenched with saturated sodiumhydrogenosulfite (10 mL) then diluted with ethyl acetate (10 mL) andwater (15 mL). The aqueous phase was extracted (4×20 mL ethyl acetate)and the combined organic layers were dried over magnesium sulfate,filtered and evaporated to give quantitatively pure diol 20 whichcrystallized when refrigerated.

¹ H NMR (CDCl₃, 400 MHz): ∂4.38 (dd, J=10, 3 Hz, 1H), 3.90-4.02 (m, 4H),3.88 (dd, J=11.7, 10 Hz, 1H), 3.51 (dd, J=11.7, 3 Hz, 1H), 3.45 (brs,2H), 1.92-2.23 (m, 2H), 1.84 (s, 3H), 1.60-1.80 (m, 2H), 1.18 (s, 3H),1.02 (s, 3H).

¹³ C NMR, CDCl₃, ∂20.93, 21.50, 23.26, 26.34, 31.61, 42.78, 64.73,64.87, 65.60, 72.23, 111.87, 132.17, 135.12.

HRMS Calcd for C₁₃ H₂₂ O₄ : 242.1518; found: 242.1518.

MS 86(100), 87 (62), 107(25), 125(44), 150(18), 167(15), 211(52),212(38), 242(15).

IR (chloroform, cm⁻¹) 3617, 3455.3, 2960.1, 2887.0, 1708.1, 1472.7,1453.6, 1428.1, 1381.6, 1356.2, 1207.9, 1139.8, 1055.1.

R_(f) =0.26 (ethyl acetate/hexanes, 1:1).

Melting point: 100°-101° C.

Preparation of aldehyde 21

To a stirred solution of diol 20 (51 mg, 0.21 mmol) andN-methylmorpholine-N-oxide (NMO, 27 mg, 0.23 mmol) was added molecularsieves (4 angstroms, powdered) and tetrapropylammonium perruthenate(TPAP, 7.4 mg, 0.1 eq, 0.021 mmol). After 10 minutes, the green colorturned to a grey-black color. The mixture was applied to a silica gelcolumn (70 mL, silica gel, 40-65μ, ethyl acetate/hexanes, 1:4) which waseluted with the same solvent to give 24.5 mg (56%) of the aldehyde 21.

¹ H NMR (CDCl₃, 400 MHz): ∂10.08 (s, 1H), 3.99 (brs, 4H), 2.40 (t, J=6.6Hz, 2H), 2.11 (s, 3H), 1.80 (t, J=6.6 Hz, 2H), 1.26 (s, 6H).

¹³ C NMR, CDCl₃, ∂18.88, 21.83, 26.17, 33.62, 41.41, 65.67, 111.54,139.30, 153.88, 192.00.

IR (neat, thin film, cm⁻¹) 2883.0, 1725.8, 1673.6, 1614.0, 1463.9,1379.0, 1266.5, 1210.4, 1144.7, 1096.3, 1050.9.

HRMS Calcd for C₁₂ H₁₈ O₃ : 210.1256; found: 210.1253.

MS 49(100), 51(27), 83(20), 86(30), 87(40), 181(3), 182(3), 183(3),209(3), 210(4), 211(5).

R_(f) =0.70 (ethyl acetate/hexanes, 1:1).

Preparation of Compound 22

To a room temperature solution of ketoketal 1 (9) (3.972 g, 20.06 mmol)in tetrahydrofuran (anhydrous, 50 mL) was added a solution of sodiumacetylide in xylene and mineral oil (18% wt, 10.7 mL, d=0.884, 35 mmol,1.75 eq) and the mixture was stirred for 5 hours under nitrogen. It wasthen diluted with ether (100 mL), washed with brine (3×100 mL). Theaqueous layers were back extracted (3×100 mL of ether) and the combinedorganic layers were dried over magnesium sulfate, filtered andevaporated. Flash chromatography of the residue (150 mL, silica gel,40-65μ, ethyl acetate/hexanes, 1:4) gave 3.365 g (74.9%) of whitecrystals of tertiary alcohol 22.

¹ H NMR (CDCl₃, 400 MHz): ∂3.89-4.03 (m, 4H), 2.40 (s, 1H), 1.93-2.04(m, 1H), 1.78 (m, 1H), 1.39-1.58 (m, 3H), 1.24 (s, 3H), 1.16 (s, 3H),1.12 (d, J=8.8 Hz, 3H).

¹³ C NMR, CDCl₃, ∂16.25, 16.93, 22.15, 26.03, 29.81, 35.78, 45.51,64.02, 65.48, 72.20, 78.23, 84.73, 112.51.

HRMS Calcd for C₁₃ H₂₀ O₃ : 224.1412; found: 224.1409.

MS 53(38), 55(38), 86(20), 99(48), 207(100), 224(16).

IR (chloroform, cm⁻¹) 3489.6, 3306.7, 2981.4, 2936.9, 2891.2, 1452.0,1390.1, 1379.6.

R_(f) =0.38 (ethyl acetate/hexanes, 1:4).

Melting point 107°-108° C. (hexanes).

Preparation of compound 23

Chromium trioxide (1 g, 10 mmol, 20 eq) was suspended in dichloromethane(10 mL) and cooled to -23° C. 3,5-Dimethylpyrazole (DMP, 0.96 g, 20 eq)was then added and the mixture was stirred 20 minutes at -23° C. Theenol triflate 2 (165 mg, 0.5 mmol) was dissolved in dichloromethane (2mL) and the solution was added to the red-brown solution of CrO₃ -DMPcomplex. After being stirred at room temperature, a pale new spotappeared on the TCL, but the mixture was mostly composed of theremaining triflate 2. No further disappearance of starting material wasobserved even after 2 days of reflux. The mixture was then cooled toroom temperature; 3 mL of 6N sodium hydroxide was added and the mixturewas stirred at 0° C. for 30 minutes. After dilution with water (20 mL)and dichloromethane (20 mL), the aqueous phase was extracted withdichloromethane (20 mL), and the combined organic layers were washedwith 0.1N hydrochloric acid (2×20 mL), brine (20 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. Flashchromatography (60 mL, silica gel, 40-65μ, ethyl acetate/hexanes, 1:5)gave 2 fractions, starting triflate (79 mg, 48%) and a fractionconstituted with 2 products (62 mg, 36%) having one of them being thedesired enone 23 constituting half of the fraction.

¹ H NMR (CDCl₃, 400 MHz): ∂3.95-4.04 (m, 4H), 2.81 (s, 2H), 1.91 (s,3H), 1.33 (s, 6H).

HRMS Calcd for C₁₂ H₁₅ O₆ F₃ : 344.0541; found: 344.0512.

R_(f) =0.34 (ethyl acetate/hexanes, 1:4).

Preparation of enyne 24

A solution of the triflate 2 (180 mg, 0.546 mmol),ethynyltributylstannane (1.092 mmol, 344 mg, 0.316 mL, 2 eq), lithiumchloride (anhydrous, 69 mg, 1.63 mmol, 3 eq) andtetrakis(triphenylphosphine) palladium(O), (Pd(PPh₃)₄, 63 mg, 0.1 eq) inanhydrous THF (3 mL) was refluxed 1 day. After being cooled to roomtemperature, the mixture was diluted with ethyl acetate (30 mL) andwashed with brine (2×50 mL). The aqueous layer was extracted with ethylacetate (2×30 mL) and the combined organic layers were dried overmagnesium sulfate, filtered and evaporated. Flash chromatography of theresidue (100 ml, silica gel, 40-65μ, 5% ether in hexanes) gave the enyne24 as a pale yellow oil (77 mg, 69%).

¹ H NMR (CDCl₃, 400 MHz): ∂3.97 (brs, 4H), 3.03 (s, 1H), 2.23 (t, J=6.6Hz, 2H), 1.90 (s, 3H), 1.76 (t, J=6.6 Hz, 2H), 1.16 (s, 6H).

¹³ C NMR, CDCl₃, ∂22.00, 23.19, 26.62, 30.35, 41.69, 64.98, 80.20,81.76, 111.17, 125.60, 141.15.

HRMS Calcd for C₁₃ H₁₈ O₂ : 206.1307; found: 206.1325.

MS 41(50), 42(50), 43(55), 49(76), 51(48), 86(100), 87(25), 105(29),119(24), 134(26), 163(12), 206(24).

IR (neat, thin film, cm⁻¹) 3302.9, 2978.4, 1466.9, 1380.8, 1356.5,1212.0, 1143.8, 1085.8, 1057.6, 992.0, 949.0, 907.2.

R_(f) =0.59 (ethyl acetate/hexanes, 1:4).

General procedure for Nozaki-Kishi couplings. Preparation of allylicalcohols 25, 26, 27 and 29 and enones 28 and 30

To a 1M solution of anhydrous chromium chloride (4-6 eq.) containing0.1% (wt) of nickel chloride in anhydrous dimethylformamide, was added a1M solution of either aldehyde 5 or benzaldehyde (1 eq.) and theiodoolefin (2-3 eq.) in anhydrous dimethylformamide. Reactions involvingE-iodocrotonitrile had to be heated at 80° C. while methylE-iodocrotonate reacted at room temperature. After 12 to 16 hours, waterwas added and the mixture was extracted with ether. After washings withwater and brine, drying over magnesium sulfate and evaporation of thesolvent, flash chromatography (ethyl acetate/hexanes, 1:2) gave allylicalcohols 25 (25), 26, 27 and 29 in 59 to 66% yield.

Regular Swern oxidation (oxalyl chloride, dimethylsulfoxide,triethylamine, dichloromethane) of allylic alcohols 27 and 29 gaveenones 28 and 30 respectively in 82% and 88% yield after flashchromatography (ethyl acetate/hexanes, 1:4).

Data for allylic alcohol 25 (25)

¹ H NMR, 400 MHz, CDCl₃, TMS, ∂1.86 (s, 3H), 5.12 (s, 1H), 5.81 (brs,1H), 7.27-7.40 (m, 5H).

¹³ C NMR, CDCl₃, ∂17.92, 76.97, 94.87, 117.03, 126.88, 128.89, 128.97,139.76, 164.01.

IR (neat, thin film) 3443.3, 3064.2, 3030.5, 2920.8, 2856.1, 2220.7,1633.3, 1493.9, 1061.4, 1019.4.

MS 51(40), 68(53), 77(86), 79(61), 105(59), 107(42), 130(36), 144(22),158(26), 172(30), 173(100).

HRMS Cacd. for C₁₁ H₁₁ ON: 173.0841; found: 173.0838.

R_(f) =0.5 (ethyl acetate/hexanes, 1:1).

Data for allylic alcohol 26

¹ H NMR, 400 MHz, CDCl₃, TMS, ∂1.97 (d, J=1.1 Hz, 3H), 3.71 (s, 3H),5.11 (s, 1H), 6.26 (rs, 1H), 7.31-7.35 (m, 5H).

¹³ C NMR, CDCl₃, ∂15.52, 51.05, 78.38, 114.63, 126.89, 128.30, 128.67,140.63, 158.75, 167.30.

IR (neat, thin film) 3463.9, 3028.4, 2949.6, 1718.9, 1653.9, 1493.3,1435.6, 1219.6, 1150.2.

MS 69(15) 85(16), 101(100), 129(20), 145(21), 188(15 ), 206(10).

HRMS Cacd. for C₁₂ H₁₄ O₃ : 206.0943; found: 206.0941.

R_(f) =0.53 (ethyl acetate/hexanes, 1:1).

Data for allylic alcohol 27

¹ H NMR (CDCl₃, 400 MHz): ∂5.60 (brs, 1H), 4.28 (dd, J=10.2, 4.1 Hz,1H), 3.91-4.01 (m, 4H), 2.11-2.47 (m, 5H), 2.08 (d, J=0.8 Hz, 3H),1.72-1.86 (m, 2H), 1.68 (s, 3H), 1.10 (s, 3H), 1.08 (s, 3H).

13C NMR, CDCl₃,∂17.63, 20.68, 22.57, 23.94, 26.55, 30.83, 34.83, 43.22,64.99, 65.04, 72.78, 93.92, 112.13, 117.29, 130.95, 132.84, 165.58.

IR (neat, thin film) 3461.6, 2956.5, 2884.1, 2218.0, 1632.9, 1475.9,1442.8, 1381.2, 1356.3, 1210.2, 1134.1, 1088.3, 1058.0.

MS 86(100), 109(40), 168(22), 196(60), 276(6), 291(8).

HRMS Cacd. for C₁₇ H₂₅ O₃ N: 291.1835; found: 291.1812.

R_(f) =0.54 (ethyl acetate/hexanes, 1:1).

Data for allylic alcohol 29

¹ H NMR (CDCl₃, 400 MHz): ∂6.04 (brs, 1H), 4.25 (dd, J=9.9, 4.6 Hz, 1H),3.93-4.01 (m, 4H), 3.71 (s, 3H), 2.11-2.47 (m, 5H), 2.19 (s, 3H),1.73-1.86 (m, 2H), 1.71 (s, 3H), 1.11 (s, 3H), 1.10 (s, 3H).

13C NMR, CDCl₃, ∂15.20, 20.71, 22.82, 23.82, 26.64, 30.91, 35.14, 43.28,50.92, 65.00, 65.04, 74.75, 112.23, 113.58, 131.59, 132.10, 160.68,167.49.

IR (neat, thin film) 3455.9, 2951.0, 1717.7, 1650.1, 1434.2, 1380.5.1355.0, 1218.4, 1147.3, 1087.8, 1057.5.

MS 86(87), 87(86), 109(58), 134(41), 168(61), 196(100), 293(28),324(17).

HRMS Cacd. for C₁₈ H₂₈ O₅ : 324.1937; found: 324.1929.

R_(f) =0.56 (ethyl acetate/hexanes, 1:1).

Data for enone 28

¹ H NMR (CDCl₃, 400 MHz): ∂6.17 (q, J=1.1 Hz, 1H), 3.92-4.01 (m, 4H),3.42 (s, 2H), 2.25 (d, J=1.1 Hz, 3H), 2.21 (t, J=6.7 Hz, 2H), 1.79 (t,J=6.7 Hz, 2H), 1.48 (s, 3H), 0.95 (s, 6H).

13C NMR, CDCl₃, ∂16.90, 20.16, 22.55, 26.64, 30.54, 38.23, 42.88, 64.95,105.4, 111.74, 115.60, 128.77, 130.92, 156.41, 196.39.

IR (neat, thin film) 2964.0, 2884.2, 2220.4, 1694.3, 1609.6, 1471.8,1359.5, 1209.9, 1143.0, 1130.8, 1088.4, 1080.4.

MS 66(48), 86(100), 87(83), 94(58), 99(90). 109(93), 190(67), 203(22),246(21), 289(100).

HRMS Calcd. for C₁₇ H₂₃ O₃ N: 289.1678; found: 289.4692.

R_(f) =0.72 (ethyl acetate/hexanes, 1:1).

Data for enone 30

¹ H NMR (CDCl₃, 400 MHz): ∂6.58 (q, J=1.4 Hz, 1H), 3.94-4.04 (m, 4H),3.80 (s, 3H), 3.46 (s, 2H), 2.27 (d, J=1.4 Hz, 3H), 2.21 (t, J=6.6 Hz,2H), 1.79 (t, J=6.6 Hz, 2H), 1.48 (s, 3H), 0.95 (s, 6H).

¹³ C NMR, CDCl₃, ∂13.88, 20.14, 22.54, 26.72, 30.55, 38.07, 42.93,51.74, 64.94, 111.92, 123.81, 129.39, 130.77, 151.60, 166.67, 199.51.

IR (neat, thin film) 2951.5, 2883.0, 1726.5, 1692.5, 1639.9, 1435.1,1356.1, 1216.0, 1087.9, 1060.0.

MS 86(100), 87(40), 99(43), 109(40), 127(42), 223(42), 236(20), 279(12),322(30).

HRMS Calc. for C₁₈ H₂₆ O₅ : 322.1780; found: 322.1779. R_(f) =0.82(ethyl acetate/hexanes, 1:1).

Discussion

A retrosynthetic analysis of taxol I total synthesis given in FIG. 1involves the following key steps:

1. Formation of the B-ring is achieved through an intramolecular ketylradical cyclization of II. This cyclization might be assisted by cyclicreductive protection of the α-dione (C₉ -C₁₀, numbering refers to taxolstructure), deprotection of which would lead to the hydroxy ketonefunctionality needed in the target.

2. Construction of the D-ring involves an intramolecular oxetaneformation via the triol (11, 12) which can be obtained from III throughan elimination--reduction process.

3. Formation of the C-ring is achieved by the Diels-Alder reactionbetween dienophile IV and diene V. The regioselectivity of thecycloaddition is controlled by the carbonyl group at C₉ on thedienophile and both oxygenated functions of the diene.

4. Dienophile IV is obtained via Nozaki-Kishi (13, 14) coupling ofiodoolefin VII and aldehyde VI followed by oxidation.

5. Preparation of aldehyde VI involves palladium (O) catalyzed coupling(15) of vinyltributylstannane and triflate VIII prepared from the knownketotetal IX (16).

In the context of this general scheme, the following steps are set forthin FIGS. 2-5:

1. A-ring synthesis and extension to the aldehyde 5 (cf. FIG. 2).

2. Preparation of the dienophile 7, Diels-Alder reaction with modelfour-carbon diene 1-methoxy-3-trimethylsilyloxy-1,3-butadiene(Danishefsky's diene), and Michael addition of a cyano fragment onto theenone function of the adduct (cf. FIG. 2).

3. Further oxidation of dienophile 7 leading to dione 13 and Diels-Alderreaction with model four-carbon diene (cf. FIG. 3).

4. Allylic oxidation of A-ring (preparation of compounds 17 and 23, cf.FIG. 4).

5. Deketalization of A-ring (preparation of compound 19, cf. FIG. 4).

6. Preparation of aldehyde 21 and acetylenic compounds 22 and 24 whichmay be valuable intermediates in other synthetic schemes toward taxol(cf. FIG. 4).

7. Extension of aldehyde 5 to the trisubstituted dienophiles 28 and 30(cf. FIG. 5).

Results

The first important intermediate is the aldehyde 5 (cf. FIG. 6) whichcontains all the functionalities needed in the A-ring except the oxygenatom at C-13 which can be introduced later through an allylic oxidationprocess (vide infra). Treatment of the known ketoketal 1 (16) withpotassium bis(trimethylsilyl)amide and N-phenyltrifluoromethanesulfonimide gave the enol triflate 2 (82%) which reactedwith vinyltributylstannane under palladium (O) catalysis (15) leading tothe diene 3 in 91% yield. Hydroboration of diene 3(9-borabicyclo[3.3.1]nonane, 94%) gave alcohol 4 which was oxidized(Swern, 94%) to the aldehyde 5. TPAP oxidation (17) of 4 gave 5 in only71% yield.

In order to study the Diels-Alder reaction for the construction of theC-ring, aldehyde 5 was extended to the disubstituted dienophile 7 (cf.FIG. 7). Grignard derivative of 2-bromopropene addition onto aldehyde 5gave the allylic alcohol 6 (89%). Addition of either the lithio or thecerio derivative gave 6 in low yields. Swern oxidation of the alcohol 6gave the enone 7 in 96% yield.

Cycloaddition of 7 with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene(Danishefky's diene) (18) in benzene (2.5 days, 125° C.) gave afteracidic work-up the enone 8 (81%) which was deketalized(p-toluenesulfonic acid, tetrahydrofuran, water, 89%) to the ene trione9. Hydrocyanation of the enone functionality of 9 with diethylaluminiumcyanide (19) gave, besides a small amount of starting material, thedesired cis cyanoketone 10 and its trans isomer in a 3:1 ratio in a 96%overall yield. Compound 10 contains 19 out of the 20 carbon atoms of thetarget. Trapping of the enolate during the Michael addition of thecyanide anion by a carbon electrophile might be an alternative to theuse of a five-carbon diene for the introduction of the carbon atom atposition 20.

Introduction of the oxygen atom at C-10 was tried starting from diene 3after bis-hydroxylation to diol 20 (vide infra) without success.Attempted selective oxidation under regular or modified Swern conditions(oxalyl chloride or trifluoroacetic anhydride, addition of triethylamineat various temperatures) (20, 21) gave the undesired hydroxy ketone.This lead us to study the oxidation of the enone 7.

Treatment of the enone 7 with potassium bis(trimethylsilyl)amide andN-(phenylsulfonyl) phenyloxaziridine (22, 23) gave the hydroxy ketone 11(87%) which did not cyclize (cf. FIG. 8) with1-methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefky's diene) (18)but lead to the transposed silylated hydroxy ketone 12 (80%). Furtheroxidation of the hydroxy ketone 11 (Swern, 69%) gave the α-dione 13which showed a much higher reactivity toward the same diene as above,giving in only 3 hrs at 80° C. and after acidic work-up the adduct 14 in95% yield. Deketalization of trione 14 gave the tetraone 15(p-toluenesulfonic acid, tetrahydrofuran, water, 79%).

Unfortunately, the α-dione functionality did not survive an attemptedhydrocyanation of compound 15. Protection of the hydroxy ketone 11 witht-butyldimethylsilyl group gave a dienophile which showed a much lowerreactivity than the simple enone 7. Thus, we studied the extension ofthe aldehyde 5 to trisubstituted dienophiles. Since the Nozaki-Kishicoupling (13, 14) of iodocrotonitrile or iodocrotonate had never beendescribed, a preliminary study of this chromium chloride promotedreaction catalyzed by nickel chloride was done with benzaldehyde (cf.FIG. 9), giving allylic alcohols 25 and 26 is about 70% yield. Thiscoupling is a new route for the preparation of Υ-hydroxy-α,β-unsaturatedesters and nitriles (24, 25). Allylic alcohols 27 and 29 were obtainedin comparable yield from aldehyde 5. These compounds were then oxidizedto the enones 28 and 30 respectively in 82% and 88% yield. We arecurrently studying the behavior of these enones in Diels-Alder reactionsas well as the further oxidation to the corresponding diones.

Besides the straightforward route to taxol skeleton described to thispoint, various functionalizations in which the most important is theallylic oxidation of the A-ring have been achieved. The presence of theside chain at position 13 is known to be indispensable for anybiological activity. A model reaction has been studied on the protectedalcohol

Alcohol 4 was silylated (t-butylchlorodimethylsilane, triethylamine,76%) to compound 16 which was oxidized to the enone 17 (48%) by actionof the complex formed with chromium trioxide and 3,5-dimethylpyrazole(10, 26). Desilylation of the enone 17 (p-toluenesulfonic acid, acetone,water, 82%) gave the hydroxy enone 18. The same conditions as above forthe allylic oxidation of 16 were applied to the enol triflate 2 whichgave compound 23 in 37% yield (cf. FIG. 10).

The ketal on A-ring showing fairly strong resistance to weak acids, amodel reaction for the deketalization was studied on alcohol 4 whichupon treatment with p-toluenesulfonic acid (tetrahydrofuran, water) gavethe hydroxy ketone 19 in quantitative yield (cf. FIG. 11).

In order to obtain intermediates similar to aldehyde 5 but containing anextra oxygen atom at C-10, bis-hydroxylation of the diene 3 (catalyticosmium tetroxide, N-methyl morpholine N-oxide, 98%) gave diol 20.Attempted selective oxidation of this diol was unsuccessful either underSwern conditions (vide supra) either upon treatment with catalytictetrapropylammonium perruthenate (17) and N-methyl morpholine N-oxide.In the later case, cleavage of the diol was observed giving aldehyde 21in 56% yield (cf. FIG. 11).

Finally, in order to study how various acetylenic intermediates could belinked to an preformed A-ring, the two following reactions wereachieved. Addition of sodium acetylide to the ketoketal 1 gave thetertiary alcohol 22 in 75% yield. Eneyne 24 was obtained in 69% yieldfrom the enol triflate 2 via palladium (O) catalyzed coupling withethynyltributylstannane (15).

Total Synthesis of Taxol as Depicted in FIG. 12

Summary: The strategy of the total synthesis of taxol depicted in FIG.12 is based on the following key steps or sequences.

1. Extension of the ketoketal 1 to the aldehyde 34 correctly oxidized atC-13, and further extension to the α-diketo dienophile 39.

2. Diels-Alder between 39 and diene 40.

3. Intramolecular pinacolic coupling of 44 giving 45, containing the ABCsubskeleton of taxol.

4. Elaboration of the triol 50 and its conversion to the hydroxy oxetane51 (11,12).

Potassium enolate of ketoketal 1 was treated with N-Phenyltrifluoromethane sulfonimide to give the enol triflate 2 which wascoupled under palladium (O) catalysis with vinyl-tri-n-butylstannaneleading to diene 3. Hydroboration of 3 with 9-BBN gives after basichydroperoxide work-up the alcohol 4 which upon treatment with TBDMSCl isconverted to the protected alcohol 16. Chromium trioxide complex with3,5-dimethylpyrazole mediated allylic oxidation of 16 gives enone 17which is reduced with borane in the presence of a catalytic amount ofchiral oxazoborolidine to give the allylic alcohol 31 . Protection ofthe alcohol function of 31 with a TBDMS group followed by selectivedesilyation of the primary hydroxyl gives alcohol 33 which is oxidizedto the aldehyde 34. Nickel chloride catalyzed chromium chloride promotedcoupling of vinyl iodide 35 with aldehyde 34 affords the allylic alcohol36 which is oxidized to the enone 37 and further oxidized to the diketodienophile 39. Diels-Alder cycloaddition of 39 with diene 40 followed byacidic work-up yields adduct 41 in which the primary silyl ether isselectively cleaved affording alcohol 42. Alternatively, fluoridemediated work-up of the Diels-Alder reaction between 39 and 40 produces42 directly. Oxidation of 42 to the aldehyde 43 followed bydeketalizaton affords 44 in which the TBDMS ether is concomitantlyremoved. Samarium diiodide promoted intramolecular coupling is assistedby both the presence of the free hydroxyl group at C-13 (numberingrefers to the taxol skeleton) and the cyclic enediolate samarium speciesformed by complexation of the diketo system at C-9,10 with excessreagent. Concomitantly, the ketone at C-5 is also reduced leading to 45.Sequential selective protection of the hydroxyl groups of 45 at C-10,C-1 (temporary) and C-13, leads to triol 46 which upon oxidationproduces 47. Stereoselective α-hydroxy directed reduction of the ketoneat C-2 of 47 leads to 48 which is sequentially protected to give 49.Reduction at C-5, oxidation of the sulfide at C-20 to the sulfoxide andits elimination upon heating, followed by the osmium tetroxide catalyzedbis-hydroxylation of the intermediate allylic alcohol produces the triol50. Accordingly to the known procedures (11,12), 50 is converted to thehydroxy oxetane 51 in which the free hydroxyl group at C-13 is releasedafter acetylation of the tertiary alcohol at C-4 and desilylation. Sidechain attachment according to known protocols followed by sequentialselective deprotection of hydroxyl groups at C-1 and C-7 produces taxol.

Route 2 Synthesis Synthesis of Compound 55

The alcohol 54 (33) (13.0 g, 58.0 mmol) was dissolved in anhydrous CH₂Cl₂ (80 mL) and the resulting solution cooled to 0° C., whereupon2,6-lutidine (19.0 mL, 17.5 g, 163 mmol) was added followed by dropwiseaddition of tert-butyldimethylsilyl trifluoromethanesulfonate (17.0 mL,19.6 g, 74.0 mmol). The solution was maintained at 0° C. for 30 minutesbefore addition of H₂ O (100 mL), and the mixture allowed to come toroom temperature. The layers were separated and the aqueous phaserepeatedly extracted with CH₂ Cl₂ (3×75 mL). The combined organic phaseswere washed with 10% CuSO₄ (aq), then dried over MgSO₄ and the solventremoved in vacuo. The resulting oil was chromatographed (5% Et₂ O inhexanes) to yield 55 (19 g, 56 mmol, 97%).

TLC (20% EtOAc in hexanes): RF=0.55.

HRMS m/z (M⁺) for C₁₉ H₃₄ O₃ Si calcd. 338.2275, found 338.2282.

IR (film): 1665(w), 1251(s), 1106(s), 1090(s), 1071(s), 812(m), 801(m)cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz): ∂5.27 (brs, 1H), 3.99-3.88 (m, 4H), 3.55 (dd,J=11.9, 3.7 Hz, 1H), 2.49 (dq, J=14.0, 3.1 Hz, 1H), 2.14 (dd, J=14.0,2.9 Hz, 1H), 2.20-2.10 (m, 1H), 2.03-1.97 (m, 1 H), 1.88 (dt, J=13.3,3.4 Hz, 1H), 1.76 (qd, J=13.7, 4.2 Hz, 1H), 1.71-1.66 (m, 2H), 1.61-1.53(m, 1H), 1.32 (td, J=13.5, 4.3 Hz, 1H), 1.05 (s, 3H), 0.88 (s, 9H), 0.04(s, 3H), 0.03 (s, 3H).

¹³ C NMR (CDCl₃, 100 MHz): ∂139.4, 121.4, 109.5, 78.1, 64.4, 64.2, 41.3,39.6, 35.7, 30.9, 27.6, 25.9, 24.8, 18.0, 17.0, -4.0, -4.8.

Synthesis of Compound 56

The alkene 55 (1.964 g, 5.81 mmol) was dissolved in anhydrous THF: (20mL) and cooled to 0° C., whereupon 1.0M BH₃ THF (5.9 mL, 5.9 mmol) wasadded dropwise to the stirred mixture. The mixture was allowed to cometo room temperature and stirred overnight. After cooling to 0° C., H₂ O(0.2 mL) was added dropwise, followed immediately by 2.5 ml of 3M NaOHand subsequently 2.5 mL of 30% H₂ O₂ (aq). The ice bath was removed andthe mixture stirred for 3.5 h. After addition of Et₂ O (100 mL) and H₂ O(100 mL), the layers were separated. The aqueous layer was extractedrepeatedly with Et₂ O (4×50 mL), and the combined organic layers washedwith brine. After concentration in vacuo to a viscous oil, the crudeproduct was dissolved in undistilled CH₂ Cl₂ (100 mL) and treated withpowdered 4 A molecular sieves (9 g; Aldrich), 4-methylmorpholine N-oxide(2.7 g), and tetrapropylammonium perruthenate catalyst (120 mg) whileunder N₂. After 2 hours, the mixture was filtered through Celite andconcentrated in vacuo to a dark green oil. The crude product wasdissolved in MeOH (100 mL) and treated with 20 mL of 3% NaOMe in MeOHfor 10 h. After concentration in vacuo, the resulting oil was dissolvedin Et₂ O (100 mL) and washed with H₂ O (2×100 mL) and brine. The Et₂ Olayer was dried (MgSO₄), concentrated in vacuo, and chromatographed (30%Et₂ O in hexanes) to give trans-fused ketone 56 as the major product(1.571 g, 4.43 mmol, 76% from the alkene).

TLC (20% EtOAc in hexanes): Rf=0.34.

HRMS m/z (M⁺) for C₁₉ H₃₄ O₄ Si calcd. 354.2226, found 354.2214.

IR (film): 1716(s), 1110(s), 1093(s), 1051(s) cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz): ∂3.97-3.87 (m, 4H), 3.78 (dd, J=11.1, 5 Hz,1H), 2.46 (dd, J=12.3, 3.7 Hz, 1H), 2.41-2.27 (m, 2H), 2.00-1.58 (m,7H), 1.42 (td, J=13.4, 4.9 Hz, 1H), 0.88 (s, 9H), 0.78 (s, 3H), 0.07 (s,6H).

¹³ C NMR (CDCl₃, 100 MHz): ∂210.4, 109.0, 77.2, 64.3, 64.2, 52.2, 42.4,38.9, 35.1, 30.7, 30.5, 29.6, 25.8, 18.0, 10.6, -4.1, -4.8.

Synthesis of Compound 57

The ketone 56 (6.00 g, 16.9 mmol) was dissolved in anhydrous THF (100mL) and cooled to -78° C. Solid potassium bis(trimethylsilyl)amide (4.2g, 21 mmol; Aldrich) was weighed out separately under a N₂ atmosphere,dissolved in anhydrous THF (50 mL), and transferred via cannula to thecooled ketone solution. After 30 min, solidN-phenyltrifluoromethanesulfonimide (6.68 g, 18.7 mmol) was added in oneportion. The mixture was maintained at -78° C. for 1 h, after which H₂ O(40 mL) was added and the resulting mixture was allowed to come to roomtemperature. Upon addition of Et₂ O (100 mL), the layers were separated.The aqueous layer was re-extracted with Et₂ O (5×80 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, andconcentrated in vacuo. The resulting oil was chromatographed (1:1 CH₂Cl₂ : hexanes) to give pure enol triflate 57 (6.68 g, 13.74 mmol, 81%).

TLC (1:1 CH₂ Cl₂ : hexanes ): Rf=0.37.

HRMS m/z (M⁺) for C₂₀ H₃₃ O₆ SF₃ Si calcd. 486.1719, found 486.1735.

IR (film): 1686 (w), 1420(s), 1210(s), 1143(s), 878(s), 838(s) cm⁻¹.

¹ HNMR (CDCl₃, 400 MHz): ∂5.61 (td, J=5.1, 2.9 Hz, 1H), 3.99-3.91 (m,4H), 3.54 (dd, J=9.4, 6.4 Hz, 1H), 2.67 (d quintet, J=13.5, 3.1 Hz, 1H),2.35 (dtd, J=17.8, 6.0, 2.8 Hz, 1H), 2.14 (dqd, J=17.9, 4.5, 2.8 Hz,1H), 1.84-1.76 (m, 3H), 1.67 (d quintet, J=13.5, 2.5 Hz, 1H), 1.59 (t,J=13.3 Hz, 1H), 1.24 (td, J=14.7, 4.6 Hz, 1H), 0.88 (s, 3H), 0.87 (s,9H), 0.04 (s, 3H), 0.03 (s, 3H).

¹³ CNMR (CDCl₃, 100 MHz): ∂149.0, 130.0, 116.2, 108.4, 74.3, 64.5, 64.2,42.7, 39.1, 33.0, 31.3, 30.9, 30.6, 25.8, 18.0, 9.0, -4.1, -4.8.

Synthesis of Compound 58

The enol triflate 57 (2.865 g, 5.895 mmol) was dissolved in anhydrousDMF (25 mL) and to this solution was added N, N-diisopropylethylamine(2.8 mL, 2.1 g, 16 mmol) and powdered 4 A molecular sieves (1.1 g). Tothis slurry was added anhydrous MeOH (10 mL, 7.91 g, 247 mmol). Thesystem was purged with carbon monoxide for 5 min, whereupontriphenylphosphine (240 mg, 0.916 mmol) and Pd(OAc)₂ (102 mg, 0.454mmol) were added. The purging was discontinued, and the system was keptunder ca. 2 psi of CO for 3-4 hours. The slurry was filtered throughCelite and H₂ O (50 mL) was added to the filtrate, followed by Et₂ O (65mL) (The crude ¹ H NMR showed the presence of a minor product, thoughtto be the cis-fused isomer). After separation, the aqueous layer wasre-extracted with Et₂ O (4×30 mL). The combined organic layers werewashed with brine, dried over MgSO₄, and concentrated in vacuo.Chromatography (15% Et₂ O in hexanes) yielded pure methyl ester 58(1.702 g, 4.298 mmol, 73%).

TLC (40% EtOAc in hexanes): Rf=0.76 (UV active).

HRMS m/z (M⁺) for C₂₁ H₃₆ O₅ Si calcd. 396.2332, found 396.2345.

IR (film): 1718 (s), 1637(w), 1250(s), 1110(s), 1071(s) cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz): ∂6.54 (quintet, J=2.6 Hz, 1H), 4.03-3.91(complex, 4H), 3.68 (s, 3H), 3.50 (dd, J=9.6; 6.4 Hz, 1H), 2.54 (dquintet, J=13.3, 2.9 Hz, 1H), 2.32 (m, 2H), 2.14 (m, 1H), 1.82 (m, 2H),1.68 (m, 1H), 1.40 (t, J=7.2 Hz, 1H), 1.25 (m, 1H), 0.89 (s, 9H), 0.82(s, 3H), 0.02 (s, 6H).

¹³ C NMR (CDCl₃, 100 MHz): ∂167.8, 136.5, 132.9, 109.1, 74.8, 64.3,64.1, 51.4, 41.1, 37.7, 33.4, 33.1, 31.5, 31.0, 25.8, 20.7, 18.0, 9.0,-4.1, -4.8.

Synthesis of Compound 59

The methyl ester 58 (3.97 g, 10.0 mmol) was dissolved in anhydroushexanes (50 mL) with gentle warming. The solution was cooled to -78° C.and treated with 30 mL of 1.0M DIBAL in hexanes (Aldrich). After 1.5 h,the reaction mixture was quenched with H₂ O (60 mL) followed by 1N HCl(40 mL) and allowed to warm to room temperature. The mixture wasextracted repeatedly with EtOAc (4×100 mL). The organic layer was washedwith brine (2×50 mL), dried over MgSO₄, and concentrated in vacuo to asemi-crystalline product. Chromatographic purification (5% MeOH in CH₂Cl₂) led to the allylic alcohol 57 (3.66 g, 9.95 mmol, 99%) as a whitesolid (mp=92°-94° C.).

TLC (5% MeOH in CH₂ Cl₂): Rf=0.32.

HRMS m/z (M+) for C₂₀ H₃₆ O₄ Si calcd. 368.2383, found 368.2377.

IR (film): 3416(s), 1472 (m), 1360(m), 1250(m), 1106 (s), 1072(s),872(m), 836(s), 774(s) cm⁻¹.

¹ HNMR (CDCl₃, 400 MHz): ∂5.57 (m, 1H), 4.03-3.92 (complex, 6H), 3.53(dd, J=9.8, 6.5 Hz, 1H), 2.49 (br d, 1H), 2.23 (br d, 1H), 2.02 (m, 1H),1.90 (dt, J=12.9, 2.5 Hz, 1H), 1.83 (dq, J=13.0, 2.5 Hz, 1H), 1.75 (dd,J=13.7, 4.7 Hz, 1H), 1.67 (d quintet, J=13.8, 2.5 Hz, 1H), 1.56 (t,J=13.2 Hz, 1H), 1.21 (td, J=12.8, 4.5 Hz, 1H), 0.87 (s, 9H), 0.79 (s,3H), 0.02 (s, 6H). ¹³ CNMR (CDCl₃, 100 MHz): ∂137.9, 123.1, 109.4, 75.8,65.1, 64.3, 64.2, 41.7, 37.4, 33.3, 33.2, 32.2, 30.8, 25.8, 18.0, 8.9,-4.0, -4.8.

Synthesis of Compound 60

The allylic alcohol 59 (3.56 g, 9.67 mmol) was dissolved in 200 mL ofacetone/H₂ O (8/1), and to this solution was 4-methylmorpholine N-oxide(2.4 g, 20 mmol). The system was purged with N₂ for 10 minutes before 5mL of a 0.1M solution of OsO₄ in tert-butyl alcohol was added. Afterstirring for 12 h at room temperature the reaction flask was cooled to0° C. and 50 mL of 10% NaHSO₃ (aq) was added. The resulting brown slurrywas extracted with EtOAc (5×100 mL). The combined extracts were washedwith brine, dried over MgSO₄ and concentrated in vacuo to a light brownsolid. ¹ HNMR analysis of the crude product, showed a 4:1 mixture oftriols. Chromatography (5% MeOH in CH₂ Cl₂) gave the major triol 60(2.56 g, 6.36 mmol, 66%) as a white crystalline powder (mp= 117°-118°C.).

TLC (10% MeOH in CH₂ Cl₂): Rf=0.39 (Rf of minor triol=0.32).

IR (film): 3441(s), 1256(m), 1102(s), 864(m), 835(m) cm⁻¹.

HRMS m/z (M⁺) for C₂₀ H₃₈ O₆ Si calcd. 402.2438, found 402.2447.

¹ H NMR (CDCl₃, 400 MHz): ∂4.00 (br s, 1H), 3.98-3.90 (m, 4H), 3.77 (dd,J=11.5, 5.5 Hz, 1H), 3.56 (m, 2H), 2.06 (dd, J=14.7, 2.7 Hz, 1H), 1.87(m, 2H), 1.80-1.70 (M, 2H), 1.62 (m, 2H), 1.52 (t, J=13.2 Hz, 1H), 1.29(td, J=12.6, 6.4 Hz, 1H), 0.87 (s, 9H), 0.82 (s, 3H), 0.06 (s, 3H), 0.04(s, 3H).

¹³ C NMR (CDCl₃, 100 MHz): ∂109.3, 73.7, 69.4, 64.3, 64.2, 62.0, 42.5,38.8, 38.0, 34.8, 30.9, 30.1, 25.9, 18.0, 12.3, -4.0, -4.8.

Synthesis of Compound 61

The triol 60 (536 mg, 1.33 mmol) was dissolved in CH₂ Cl₂ (45 mL) andanhydrous pyridine (1.15 mL, 14.2 mmol) and the resulting solution wascooled to -78° C., whereupon freshly distilled chlorotrimethylsilane(0.236 mL, 1.86 mmol) was added and the mixture allowed to come to roomtemperature for 1 h. TLC monitoring (40% EtOAc in hexanes) revealed thepresence of what was presumed to be the primary trimethylsilyl etherintermediate (Rf=0.54) along with a trace amount of the disilyl etherbyproduct (Rf=0.86; primary and secondary alcohols etherified). Themixture was cooled to -78° C. and treated with trifluoromethanesulfonicanhydride (5.75 mL of a 1.0M stock solution in CH₂ Cl₂) and allowed tocome to room temperature for 1 h. TLC monitoring (40% EtOAc in hexanes)indicated complete conversion of the initial intermediate to itstriflate (Rf=0.85). The mixture was finally treated with ethylene glycol(6 mL) and refluxed for 12 h. Water (20 mL) and brine (20 mL) were addedand the layers were separated. The aqueous layer was extractedrepeatedly with CH₂ Cl₂ (6×15 mL). The combined organic layers werewashed with brine, dried over Na₂ SO₄, and concentrated in vacuo. ¹ HNMRanalysis of the crude yellow oil showed the desired oxetane 61 to be themajor product by a 6:1 margin over the migration byproduct 62. Themixture was chromatographed (gradient elution of 40% to 60% EtOAc inhexanes) to obtain pure 61 (353 mg, 0.919 mmol, 69%) as a white solid.

TLC (40% EtOAc in hexanes): Rf of 61=0.17; Rf of 62=0.30.

HRMS of 61 m/z (M⁺ +1) for C₂₀ H₃₇ O₅ Si calcd. 385.2410, found 385.2410. HRMS of 62 m/z (M⁺) for C₂₀ H₃₆ O₅ S; calcd. 384.2332, found384.2323.

IR (film) of 61: 3416(br), 1094(s), 859(s), 836(s), 774(s) cm⁻¹. IR(film) of 62: 3456(br), 1710(s), 1253(s), 1094 (vs), 863(s), 836(s),775(s) cm⁻¹.

¹ H NMR of 61 (CDCl₃, 400 MHz): ∂4.78 (dd, J=9.1, 2.2 Hz, 1H), 4.46 (d,J=7.6 Hz, 1H), 4.26 (d, J=7.6 Hz, 1H), 3.96-3.89 (m, 4H), 3.44 (dd,J=10.6, 7.24 Hz, 1H), 2.27 (ddd, J=16.3, 9.2, 7.1 Hz, 1H), 1.88 (ddd,J=15.1, 10.7, 2.4 Hz, 1H), 1.83-1.72 (m, 2H), 1.68-1.55 (m, 5H), 1.21(s, 3H), 0.87 (s, 9H), 0.02 (s, 6H).

¹³ NMR of 61 (CDCl₃, 100 MHz): ∂108.8, 88.1, 76.4, 74.0, 64.4, 64.3,46.7, 37.6, 36.5, 30.9, 30.2, 29.7, 25.8, 18.0, 9.5, -4.0, -4.8.

¹ H NMR of 62 (CDCl₃, 400 MHz): ∂3.95-3.81 (m, 4H), 3.63-3.56 (m, 2H),2.58-2.48 (m, 3H), 1.91 (quintet, J=5.0 Hz, 1H), 1.81-1.60 (m, 5H), 1.40(td, J=13.0, 5.3 Hz, 1H), 0.85 (s, 9H), 0.72 (s, 3H), 0.05 (s, 6H).

¹³ C NMR of 62 (CDCl₃, 100 MHz): ∂213.0, 108.9, 64.3, 64.2, 62.1, 52.3,49.1, 42.9, 35.0, 33.7, 30.1, 29.4, 25.7, 17.9, 10.6, -4.1, -4.8.

Synthesis of Compound 63

Oxetane 61 (20 mg, 0.052 mmol) was dissolved in anhydrous THF (2 mL) andtreated with 1.0M tetrabutyl ammonium fluoride in THF (0.100 mL, 0.100mmol). The mixture was heated to reflux for 12 h, cooled to roomtemperature, and chromatographed directly (EtOAc as eluant) to give 63(13 mg, 0.048 mmol, 93%). Recrystallization from CHCl₃ yielded a fine,white crystalline solid from which a single crystal x-ray was obtained.

mp=232° C. (dec).

TLC (EtOAc): Rf=0.18.

HRMS m/z (M⁺) for C₁₄ H₂₂ O₅ calcd. 270.1467, found 270.1478

¹ H NMR (CDCl₃, 400 MHz): ∂4.83 (dd, J=2.9, 9.0 Hz, 1H), 4.46 (d, J=7.6Hz, 1H), 4.28 (d, J=7.5 Hz, 1H), 3.99-3.89 (m, 4H), 3.50 (m, 1H), 2.44(quintet, J=8 Hz, 1H), 1.90-1.60 (m, 6H), 1.41-1.29 (m, 2H), 1.25 (s,3H).

¹³ C NMR (CD₃ OD, 100 MHz): ∂110.1, 89.9, 77.8, 76.8, 74.4, 65.3, 65.2,47.7, 38.3, 37.6, 37.3, 32.0, 30.7, 9.9.

Synthesis of Compound 64

The ketal 61 (1.320 g, 3.438 mmol) was dissolved in 12 mL of acetone and1 mL of H₂ O. To this solution was added collidinium tosylate (0.70 g,2.4 mmol) and the mixture was heated to reflux. Due to the sluggishnessof the deketallization, more collidinium tosylate (0.60 g, 2.0 mmol) andH₂ O (1 mL) were added over a period of 120 h. The majority of startingketal was consumed during this period, as monitored by TLC (Rf of 61with EtOAc eluant=0.52; Rf of 64=0.65). The mixture was cooled to roomtemperature and concentrated in vacuo to remove most of the acetone. Tothe crude product was added H₂ O (10 mL) and EtOAc (50 mL) and thelayers were separated. The aqueous phase was repeatedly extracted withEtOAc (5×40 mL) and the combined organic phases were washed with brine,dried over MgSO₄, and concentrated in vacuo. Chromatography (40% EtOAcin hexanes) yielded pure 64 as a white solid (0.985 g, 2.897 mmol, 84%).Recrystallization from n-pentane/CH₂ Cl₂ (10/1) gave fine white needles(mp=152° C.).

IR (film): 3375(s), 1710(s), 1253(s), 1083(s), 940(m), 836(s), 772(s)cm⁻¹.

HRMS m/z (M⁺ +1) for C₁₈ H₃₃ O₄ Si calcd. 341.2148, found 341.2154.

¹ H NMR (CDCl₃, 400 MHz): ∂4.80 (d, J=7.9 Hz, 1H), 4.55 (d, J=7.8 Hz,1H), 4.27 (d, J=7.8 Hz, 1H), 3.46 (dd, J=10.6, 7.2 Hz, 1H), 2.48 (td,J=15.2, 6.4 Hz, 1H), 2.38-2.29 (m, 5H), 2.13 (dd, J=13.0, 5.3 Hz, 1H),1.94 (t, J=13.2 Hz, 1H), 1.72 (dd, J=11.5, 5.9 Hz, 1H), 1.38 (s, 3H),1.33 (td, J=13.6, 4.5 Hz, 1H), 0.88 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H).

¹³ C NMR (CDCl₃, 100 MHz): ∂210.4, 88.0, 76.1, 74.0, 48.7, 38.7, 37.7,37.6, 37.4, 36.7, 25.8, 17.9, 9.6, -4.0, -4.9.

Synthesis of Compound 65

Freshly distilled diisopropylamine (0.150 mL, 108 mg, 1.07 mmol) wascharged to a 10 mL roundbottom flask containing 3 mL anhydrous THF. Thesolution was cooled to -78° C. and treated with n-BuLi (0.355 mL, 2.5Min hexanes, 0.888 mmol). After 15 min at -78° C., ketone 64 (142 mg,0.418 mmol) in 2 mL anhydrous THF was transferred via cannula to thelithium diisopropylamide solution. After 1.5 h, chlorotrimethylsilane(0.120 mL, 103 mg, 0.945 mmol) was added and the reaction mixture warmedto room temperature for 1 h, whereupon it was poured into n-pentane/H₂ O(5 mL/5 mL) and extracted. The aqueous layer was re-extracted withn-pentane (3×5 mL). The combined organic layers were washed with brine,dried over MgSO₄, and concentrated in vacuo to the crude enol ether,which was redissolved in anhydrous acetonitrile (4 mL) at reflux. Afterdissolution of the enol ether, Pd(OAc)₂ (105 mg, 0.468 mmol) was addedand the resulting mixture maintained at reflux for 5 h. At this time,MeOH (3 mL) and K₂ CO₃ powder (200 mg, 1.45 mmol) were added whilemaintaining reflux for 1 h. After cooling to room temperature, theslurry was filtered through Celite (MeOH wash) and the filtrateconcentrated in vacuo to a yellow oil. Chromatography (3% MeOH in CH₂Cl₂) yielded the desired enone 65 (109 mg, 0.322 mmol, 77%) contaminatedwith a trace amount of an unidentified byproduct.

TLC (20% EtOAc in hexanes): Rf=0.14 (UV active).

HRMS m/z (M⁺ +1) for C₁₈ H₃₁ O₄ Si calcd. 339.1992, found 339.1986

IR (film): 3413 (s), 1681 (s), 1256 (s), 1069 (s), 837 (s), 776 (s)cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz): ∂7.12 (d, J=10.2 Hz, 1H), 5.90 (d, J=10.2 Hz,1H), 4.83 (dd, J=8.8, 1.6 Hz, 1H), 4.54 (d, J=7.8 Hz, 1H), 4.34 (d,J=7.8 Hz, 1H), 3.65 (dd, J=10.0, 7.6 Hz, 1H), 2.72 (s, 1H), 2.48-2.37(m, 3H), 2.07 (ddd, J=12.7, 6.0, 0.8 Hz, 1H), 1.93 (ddd, J=15.3, 10.0,1.9 Hz, 1H), 1.39 (s, 3H), 0.92 (s, 9H), 0.06 (s, 6H).

¹³ C NMR (CDCl₃, 100 MHz): ∂199.1, 157.2, 126.8, 87.7, 76.7, 73.4, 72.1,45.6, 37.3, 33.3, 25.8, 18.0, 11.3, -3.9, -5.0.

Synthesis of Compound 66

Alcohol 65 (144 mg, 0.426 mmol) was dissolved in 2 mL anhydrous DMF andthe resulting solution treated with imidazole (200 mg, 2.94 mmol) andtert-butyldimethylsilyl chloride (215 mg, 1.43 mmol). The mixture washeated to 80° C. for 12 h, then poured into Et₂ O (10 mL) and H₂ O (5mL) and extracted. The aqueous layer was re-extracted with Et₂ O (5×10mL). The combined organic phases were washed with brine, dried overMgSO₄, and concentrated in vacuo. Chromatography (5% EtOAc in hexanes)yielded the desired silyl ether 66 (110 mg, 0.243 mmol, 57%) along withstarting alcohol 65 (25 mg, 0.074 mmol, 17% recovered).

TLC (5% EtOAc in hexanes): Rf=0.18 (UV active).

HRMS m/z (M⁺ +1) for C₂₄ H₄₅ O₄ Si₂ calcd 453.2857, found 453.2905.

IR (film): 1684(s), 1255(s), 1094(s), 836(s), 775(s) cm⁻¹. ¹ H NMR(CDCl₃, 400 MHz): ∂7.10 (d, J=10.0 Hz, 1H), 5.89 (d, J=10.1 Hz, 1H),4.89 (d, J=8.0 Hz, 1H), 4.42 (d, J=7.3 Hz, 1H), 4.37 (d, J=7.2 Hz, 1H),3.64 (dd, J=9.5, 7.9 Hz, 1H), 2.42-2.34 (m, 3H), 2.02 (t, J=8.0 Hz, 1H),1.92 (ddd, J=15.5, 9.6, 1.4 Hz, 1H), 1.39 (s, 3H), 0.92 (s, 9H), 0.87(s, 9H), 0.13 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H).

¹³ C NMR (CDCl₃, 100 MHz): ∂198.9, 157.0, 126.7, 86.6, 76.6, 74.7, 72.3,47.2, 41.3, 37.5, 33.2, 25.7, 25.5, 18.0, 17.9, 11.2, -3.0, -3.1, -3.9,-5.1.

Synthesis of Compound 67

To alcohol 65 (85 mg, 0.251 mmol) in 2 mL anhydrous CH₂ Cl₂ was addedanhydrous pyridine (0.026 mL, 25 mg, 0.32 mmol) at 0° C. followed bychlorotrimethylsilane (0.036 mL, 31 mg, 0.28 mmol). The reaction mixturewas warmed to room temperature for 1 h, then poured into H₂ O (5 mL) andextracted with CH₂ Cl₂ (3×15 mL). The combined CH₂ Cl₂ layers werewashed with brine, dried over MgSO₄, and concentrated in vacuo.Chromatography (5% EtOAc in hexanes) yielded pure 66 (91 mg, 0.222 mmol,88%).

TLC (40% EtOAc in hexanes): Rf=0.83 (UV active).

¹ H NMR (CDCl₃ ; 400 MHz): ∂7.09 (d, J=10.1 Hz, 1H), 5.89 (d, J=10.1 Hz,1H), 4.91 (d, J=7.5 Hz, 1H), 4.43 (dd, J=10.8 Hz, 7.6 Hz, 2H), 3.65 (dd,J=9.5, 8.0 Hz, 1H), 2.43-2.36 (m, 3H), 2.04 (t, J=8.6 Hz, 1H), 1.92(ddd, J=15.5, 9.6, 1.4 Hz, 1H), 1.39 (s, 3H), 0.92 (s, 9H), 0.16 (s,9H), 0.07 (s, 3H), 0.06 (s, 3H).

Synthesis of Compound 68

To enone 67 (6 mg, 0.0146 mmol) dissolved in anhydrous THF (1 mL) andcooled to -78° C. was added dropwise potassium bis(trimethylsilyl)amide(0.035 mL of 0.5M solution in toluene, 0.0175 mmol). After 30 min ayellow color developed, and a solution of N-phenylsulfonylphenyloxiziridine (10 mg, 0.038 mmol) in THF (1 mL) was added slowlydown the side of the flask. After 10 min, H₂ O (1 mL) was added and themixture was allowed to warm to room temperature for 30 min, whereupon itwas poured into EtOAc (5 mL) and brine (5 mL) in a separatory funnel andsubsequently extracted. The aqueous phase was re-extracted with EtOAc(6×5 mL). The combined organic phases were washed with brine, dried overMgSO₄, concentrated in vacuo, and chromatographed (gradient elution, 20%to 40% EtOAc in CH₂ Cl₂) to give pure diol 68 as a white solid (4 mg,0.0113 mmol, 77%).

TLC (20% EtOAc in CH₂ Cl₂): Rf=0.13 (UV active).

IR (film): 3461(s), 1691(s), 1255(m), 1157(s), 1100(s), 1045(m), 869(s),838(s), 776(s) cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz): ∂7.20 (d, J=10.1 Hz, 1H), 6.01 (d, J=10.1 Hz,1H), 4.88 (d, J=8.5 Hz, 1H), 4.61 (d, J=7.2 Hz, 1H), 4.56 (d, J=7.3 Hz,1H), 4.53 (dd, J=13.0, 1.2 Hz, 1H), 4.03 (s, 1H), 3.76 (d, J=1.3 Hz,1H), 3.68 (dd, J=9.6, 7.7 Hz, 1H), 2.43 (quintet, J=7.8 Hz, 1H), 2.07(d, J=13.0 Hz, 1H), 1.93 (ddd, J=15.4, 9.8, 1.4 Hz, 1H), 1.53 (s, 3H),0.92 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).

13C NMR (CDCl₃, 100 MHz): ∂199.3, 158.9, 123.0, 85.0, 76.8, 72.8, 71.9,70.4, 52.0, 43.0, 37.2, 25.7, 18.0, 11.7, -3.9, -5.1.

Synthesis of Compound 69

Freshly distilled diisopropylamine (0.018 mL, 13 mg, 0.13 mmol) wascharged to a dry 5 mL roundbottom flask containing 1 mL anhydrous THF.The solution was cooled to -78° C. and treated with n-BuLi (0.032 mL of2.5M in hexanes, 0.080 mmol). After 15 min at -78° C., enone 15 (18.0mg, 0.0398 mmol), dissolved in 1 mL THF, was transferred into thelithium diisopropylamide solution via cannula. After maintaining at -78°C. for 45 min, chlorotrimethylsilane (0.015 mL, 13 mg, 0.12 mmol) wasadded and the reaction mixture allowed to come to room temperature for 1h, whereupon it was poured into n-pentane (5 mL) and H₂ O (5 mL) andextracted. The aqueous layer was re-extracted with n-pentane (3×5 mL)and the combined organic layers were washed with brine, dried overMgSO₄, and concentrated in vacuo. The crude product was dissolved inanhydrous CH₂ Cl₂ (1 mL) and to the resulting solution was addedanhydrous NaHCO₃ powder (20 mg, 0.24 mmol). The slurry was cooled to-78° C. and purged with ozone until a light blue color persisted,whereupon excess ozone was purged with N₂. Triphenylphosphine (27 mg,0.12 mmol) was added and the mixture was allowed to come to roomtemperature for 1.5 h, at which time it was filtered through cotton andconcentrated in vacuo to a yellow oil. Chromatography (CH₂ Cl₂ aseluant) yielded dialdehyde 69 (6.3 mg, 0.014 mmol, 36%).

TLC (CH₂ Cl₂): Rf=0.27.

HRMS m/z (M⁺ +1) for C₂₂ H₄₃ O₅ Si₂ calcd 443.2650, found 443.2613.

IR (film) 2723(w), 1728(s), 1472(m), 1257(s), 1174(m), 1098(s), 837(s),777(s) cm⁻¹.

¹ H NMR (CDCl₃, 400 MHz): ∂9.66 (s, 1H), 9.60 (d, J=0.4 Hz, 1H), 4.90(dd, J=8.3, 2.0 Hz, 1H), 4.63 (dd, J=7.4, 1.0 Hz, 1H), 4.36 (d, J=7.4Hz, 1H), 4.00 (dd, J=9.2, 6.6 Hz, 1H), 2.97 (s, 1H), 2.31 (ddd, J=15.1,8.2, 6.6 Hz, 1H), 1.94 (ddd, J=15.3, 9.2, 2.2 Hz, 1H), 1.52 (s, 3H),0.89 (s, 9H), 0.85 (s, 9H), 0.19 (s, 3H), 0.18 (s, 3H), 0.03 (s, 3H),-0.02 (s, 3H).

¹³ C NMR (CDCl₃, 100 MHz): ∂206.4, 200.2, 87.1, 79.1, 73.2, 71.7, 62.0,51.5, 36.0, 25.5, 17.8, 10.8, -2.9, -4.2, -5.3.

Discussion

This disclosure presents a synthesis of a potential C,D-ring fragment of1, starting from the Wieland-Miescher ketone (27), with appendages forthe potential elaboration of the remaining A and B rings.

A retrosynthetic analysis of 1 is given in FIG. 13. Functional groupinterchange yields the general structure I which is the product of anintra-molecular Diels-Alder cycloaddition of II for the simultaneousconstruction of rings A and B (28). Cycloaddition precursor II isassembled by three main pathways as designated by bond cleavages givenin the Figure, i.e. pathway a, b+c, or a+c.

KEY: For all R_(a), a=1, 2, 3 . . . , R=H, acyl, alkyl, aryl, TBS, TES,TMS, and/or TBDPS unless otherwise specified. For all X_(a), a=1, 2, 3 .. . , X=H,H; H,OR; O,O; OCH₂ CH₂ O; and/or SCH₂ CH₂ CH₂ S unlessotherwise specified.

Bond a would result from a nucleophilic attack of VIII (M=metal; X₂=SCH₂ CH₂ CH₂ S; H,H) (29) upon aldehyde III, which in turn is derivedfrom degradation of olefin VI. The degradation precursor VI is theproduct of methyllithium addition to the central intermediate, enoneVII. Bond b is formed by addition of the known metallated diene IX tothe aldehyde function in V, which is the homologation product derivedfrom aldehyde IV. Introduction of the dienophile (bond c) results fromaddition of a two carbon acyl-anion equivalent such as X.

An alternative route invokes an entirely different construction of thegeneral tetracyclic intermediate I in which the B-ring is formed via areductive coupling of the dicarbonyl intermediate XI (FIG. 14). Assemblyof the cyclization precursor XI is achieved by coupling a pre-formedA-ring synthons XII or XIII (30). Pathway a represents Nozaki-Kishi (13,14) coupling of enol triflate with aldehyde V. Alternatively, pathway bis possible by nucleophilic addition of XIII (M=metal; X₁ =H,H; X₂ =SCH₂CH₂ CH₂ S; X₅ =OCH₂ CH₂ O) to aldehyde IV.

All of the aforementioned routes require the synthesis of intermediatescontaining C,D-ring system and equipped with appropriate functionalityto elaborate the remaining A and B rings.

Results

We began on the assumption that the ketone (27) offered a viablesubstrate for the construction of the C,D portion of 1, given its readyconversion to 54 (FIG. 15) (for ketone production, see (31, 32); fordeconjugative ketalization and hydroboration/oxidation, see (33), andits availability in optically active form, see (34, 35, 36, 37)). Theequatorial secondary alcohol of 54 (a pro C-7 hydroxyl in the C-ringof 1) was protected as the t-butyldimethylsilyl (TBS) ether (38) to give55. The olefin of 55 was hydroborated and oxidized according to thereported protocol (33) to give a mixture of diastereomeric alcohols.Tetrapropylammonium perruthenate catalyzed oxidation (39, 40) gave thecis and trans-fused ketones which converged to the trans 56 after basecatalyzed equilibration. For the purpose of one carbon homologation, 56was converted to the enol triflate 57 by O-sulfonylation of itspotassium enolate with N-phenyltrifluoromethane sulfonimide (41, 42,43). Palladium catalyzed carbomethoxylation (44) of 57 yielded theunsaturated ester 58, which was readily reduced with DIBAH to thecorresponding allylic alcohol 59. Osmylation of 59 under catalyticconditions yielded a 4:1 diastereomeric ratio of triols, 60 being themajor product.

After isolation by flash chromatography (8), triol 60 was converted inone pot to oxetane 61 (45). Careful silylation of the primary alcoholwas achieved with TMSCl/pyridine in CH₂ Cl₂ (-78° C. to rt) as monitoredby TLC; the solution was cooled back to -78° C. and treated withtrifluoromethanesulfonic anhydride. After warming to rt, TLC indicatedthat the secondary alcohol had been converted to its triflate. Whilefluoride treatment tended to promote the migration of the hydroxymethylfunction to give 62, it was observed that alcoholic desilylation yieldedoxetane 61 as the major product, the best result being achieved withethylene glycol (analysis of the crude ¹ H NMR spectrum indicated a ca.6:1 ratio of 61:63). The desired oxetane 61 was isolated in 69% overallyield from triol 60. Removal of the TBS ether with tetrabutylammoniumfluoride gave diol 63, of which a single crystal x-ray was obtainedconfirming the structure. It will be noted that compounds 61 and 63 arethe first synthesized subunits containing the full complement of oxygenscorresponding to the C,D section of taxol 1.

Having constructed pro C and D rings of 1, we sought to unravelappendages useful to the introduction of rings A and B. To this end, theketal of 61 was removed under mildly acidic conditions (collidiniumtosylate) to maintain the integrity of both the TBS ether and theoxetane ring. Ketone 64 was subsequently converted to the correspondingenone 65 by way of its silyl enol ether (46) with Pd(OAc)₂ (47, 48). Thetertiary alcohol of 65 was protected as the TBS ether, though only underforcing conditions (DMF/imidazole/80° C./12 h), with an excess of TBSClto give 66. Degradation of 66 to dialdehyde 69 was accomplished byozonolysis of the silyl dienol ether, albeit in low isolated yield(36%).

With a view to obtaining the needed oxygenation at C-2, and in theinterest of exploring alternative degradative pathways, we studied theoxidation of the enone system. The tertiary alcohol of 65 was readilyconverted to the corresponding TMS ether 68. The potassium dienolate of68 was generated with potassium bis(trimethylsilyl)amide andsubsequently treated with the Davis oxaziradine to give diol 69 afteraqueous workup. Formally, C-4 of 69 can be viewed as corresponding instereochemistry to C-2 of 1.

Total Synthesis of Taxol from Dialdehyde 18 (FIG. 16)

Selective ketalization of the less hindered aldehyde of 69 gives 70.Addition of the lithiodithiane VII (X₂ =SCH₂ CH₂ CH₂ S; M=Li) followedby Swern oxidation yields 71. Release of the ketal of 71 to aldehyde 72followed by addition of the vinyllithium X (R₁ =MOM; M=Li) produces theDiels-Alder precursor 73. Upon heating, 73 will cyclize to the tricyclic74. Stereoselective reduction of the less hindered ketone of 74 yields75 after benzoylation of the newly generated (α) secondary alcohol.Allylic oxidation in the A-ring of 75, followed by Swern oxidation ifnecessary, gives enone 76. The A-ring carbonyl reduces to the αconfiguration using a bulky borohydride. Subsequent benzyl protectionand Raney nickel reduction of the thioketal produces 77. Franklin Davishydroxylation of the potassium enolate of ketone 77 gives thecorresponding hydroxy ketone in which the oxaziridine approaches fromthe convex face. After fluoride induced desilyation with TBAF,peracetylation yields 78. Hydrogenolysis of the benzyl ether andsubsequent side chain coupling produces 79. The acetate at C-7 isselectively removed to 80, which in turn is doubly deprotected bysimultaneous removal of the MOM and EE groups to give taxol.

Simple Mimics of Taxol

In FIG. 17 are given syntheses of simple taxol mimics which contain twocritical features of taxol itself, namely the side chain and theacetoxyoxetane.

Acetylation of 64 gives 81. Reduction of the ketone of 81 with a bulkyhydride (L-selectride) produces alcohol 82. Coupling of the side-chainusing the method of Denis et al. (49) yields mimic 85 after removal ofthe TBS and EE groups. The procedures are the same for the unsaturatedseries (65 to 90).

Diol 68 is benzoylated at the less hindered secondary alcohol to give91, leaving the tertiary position open to subsequent acetylation,yielding 92. The same reduction/coupling/deprotection sequence describedabove is applied to 92 giving mimic 96.

References

1. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Loggan, P.; McPhail, A. T.J. Am. Chem. Soc. 1971, 93, 2325.

2. Swindell, C. S. Org. Prep. Procedures Int. 1991, 23, 465-543.

3. Blechert, S.; Guenard, D. The Alkaloids, Academic Press, 1990, 39,195-238.

4. Rowinsky, E. K.; Cazenave, L. A.; Donehower, R. C. J. Natl. CancerInst. 1990, 82, 1247.

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7. Yadav, J. S.; Ravishankar, R. Tetrahedron Letters, 1991, 32, 2629.

8. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

9. Ketoketal 1 was prepared following procedure given in ref. 16 fromthe corresponding diketone obtained by condensation of the enamine of2-methyl-3-pentanone with acryloyl chloride. Hargreaves, J. R.;Hickmott, P. W.; Hopkins, B. J. J. Chem. Soc. 1968, 2599.

10. Kende, A. S.; Johnson, S.; Sanfilippo, P.; Hodges, J. C.; Jungheim,L. N. J. Am. Chem. Soc. 1986, 108, 3513.

11. Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron, 1991,47, 9823.

12. Magee, T. V., personal communication.

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22. Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org.Chem. 1984, 49, 3241.

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27. Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215.

28. As presented here, the cycloaddition product would require anallylic oxidation step for the introduction of the oxygenation at C-13(X₁), though it may be desirable to have it in the diene prior tocycloaddition.

29. An obvious precursor to this nucleophile has been synthesized inthese laboratories by Dr. Richard C. A. Isaacs; specifically VIII (M=H;X₂ =O,O).

30. Syntheses of XII (X₁ =H,H; X₅ =OCH₂ CH₂ O and O,O and XIII (M=H; X₁=H,H; X₅ =OCH₂ CH₂ O) have been achieved in these laboratories by Dr.Yves Queneau.

31. Boyce, C. B. C.; Whitehurst, J. S. J. Chem. Soc. 1960, 2680.

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46. The free tertiary hydroxyl served, as the lithium alcoholate, todirect the lithium enolate formation to the regiochemically desiredposition. (When the alcohol was silylated, a significant amount of theundesired enone was formed). The lithio-dianion was subsequently trappedwith excess TMSCl to give the disilyl enol ether. During the course ofsubsequent oxidation, the majority of the tertiary silyl ether wasconcomitantly removed. After consumption of starting material (TLC),MeOH and K₂ CO₃ were added to complete the desilyation process to give65.

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What is claimed is:
 1. A compound having the structure: ##STR218##wherein X is H, OH, O or OSiR₃ ; Y is --OCH₂ CH₂ O--; and R is an alkylor aryl group.
 2. A compound having the structure: ##STR219## whereineach X is independently the same or different and is H, OH, O or OSiR₃ ;Y is --OCH₂ CH₂ O--; Z is OH, O or OTMS; E is H, CN, CO₂ R, CHO or CH₂OR'; R' is H, COR, R or SiR₃ ; and R is an alkyl or aryl group.
 3. Acompound having the structure: ##STR220## wherein each X isindependently the same or different and is H, OH, O or OSiR₃ ; Y is--OCH₂ CH₂ O--; and E is H, CN, CO₂ R, CHO or CH₂ OR'; R¹ is H, OH,OCOR, OR or OSiR₃ ; R² is H, CH₂ OSiR₃, CH₂ SR or CH₂ SOR; R' is H, COR,R or SiR₃ ; and R is an alkyl or aryl group.